67 results on '"Wexler, Ruth R."'
Search Results
2. Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure.
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Wei Meng, Zulan Pi, Brigance, Robert, Rossi, Karen A., Schumacher, William A., Bostwick, Jeffrey S., Gargalovic, Peter S., Onorato, Joelle M., Luk, Chiuwa E., Generaux, Claudia N., Tao Wang, Wexler, Ruth R., and Finlay, Heather J.
- Published
- 2021
- Full Text
- View/download PDF
3. Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists.
- Author
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Zulan Pi, Johnson, James A., Wei Meng, Phillips, Monique, Schumacher, William A., Bostwick, Jeffrey S., Gargalovic, Peter S., Onorato, Joelle M., Generaux, Claudia N., Tao Wang, Yan He, Gordon, David A., Wexler, Ruth R., and Finlay, Heather J.
- Published
- 2021
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- View/download PDF
4. Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate.
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Johnson, James A., Kim, Soong-Hoon, Jiang, Ji, Phillips, Monique, Schumacher, William A., Bostwick, Jeffrey S., Gargalovic, Peter S., Onorato, Joelle M., Luk, Chiuwa E., Generaux, Claudia, He, Yan, Chen, Xue-Qing, Xu, Carrie, Galella, Michael A., Wang, Tao, Gordon, David A., Wexler, Ruth R., and Finlay, Heather J.
- Published
- 2021
- Full Text
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5. Factor XIa Inhibitors as New Anticoagulants.
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Quan, Mimi L., Pinto, Donald J. P., Smallheer, Joanne M., Ewing, William R., Rossi, Karen A., Luettgen, Joseph M., Seiffert, Dietmar A., and Wexler, Ruth R.
- Published
- 2018
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- View/download PDF
6. Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
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Corte, James R., Tianan Fang, Osuna, Honey, Pinto, Donald J. P., Rossi, Karen A., Myers, Joseph E., Sheriff, Steven, Zhen Lou, Zheng, Joanna J., Harper, Timothy W., Bozarth, Jeffrey M., Yiming Wu, Luettgen, Joseph M., Seiffert, Dietmar A., Decicco, Carl P., Wexler, Ruth R., and Quan, Mimi L.
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- 2017
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7. Atropisomer Control in Macrocyclic Factor VIIa Inhibitors.
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Glunz, Peter W., Mueller, Luciano, Cheney, Daniel L., Ladziata, Vladimir, Yan Zou, Wurtz, Nicholas R., Anzhi Wei, Wong, Pancras C., Wexler, Ruth R., and Priestley, E. Scott
- Published
- 2016
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8. Discovery of Novel P1 Groupsfor Coagulation FactorVIIa Inhibition Using Fragment-Based Screening.
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Cheney, Daniel L., Bozarth, Jeffrey M., Metzler, William J., Morin, Paul E., Mueller, Luciano, Newitt, John A., Nirschl, Alexandra H., Rendina, Alan R., Tamura, James K., Anzhi Wei, Xiao Wen, Wurtz, Nicholas R., Seiffert, Dietmar A., Wexler, Ruth R., and Priestley, E. Scott
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- 2015
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9. Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y1Antagonists as NovelAntiplatelet Agents.
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Yang, Wu, Wang, Yufeng, Lai, Amy, Qiao, Jennifer X., Wang, Tammy C., Hua, Ji, Price, Laura A., Shen, Hong, Chen, Xue-qing, Wong, Pancras, Crain, Earl, Watson, Carol, Huang, Christine S., Seiffert, Dietmar A., Rehfuss, Robert, Wexler, Ruth R., and Lam, Patrick Y. S.
- Published
- 2014
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10. Tetrahydroquinoline Derivativesas Potent and SelectiveFactor XIa Inhibitors.
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Quan, Mimi L., Wong, Pancras C., Wang, Cailan, Woerner, Francis, Smallheer, Joanne M., Barbera, Frank A., Bozarth, Jeffrey M., Brown, Randi L., Harpel, Mark R., Luettgen, Joseph M., Morin, Paul E., Peterson, Tara, Ramamurthy, Vidhyashankar, Rendina, Alan R., Rossi, Karen A., Watson, Carol A., Wei, Anzhi, Zhang, Ge, Seiffert, Dietmar, and Wexler, Ruth R.
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- 2014
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11. Factor Xa Inhibitors: Next-Generation Antithrombotic Agents.
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Pinto, Donald J. P., Smallheer, Joanne M., Cheney, Daniel L., Knabb, Robert M., and Wexler, Ruth R.
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- 2010
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12. Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa--Tissue Factor Complex.
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Xiaojun Zhang, Glunz, Peter W., Johnson, James A., Wen Jiang, Jacutin-Porte, Swanee, Ladziata, Vladimir, Yan Zou, Phillips, Monique S., Wurtz, Nicholas R., Parkhurst, Brandon, Rendina, Alan R., Harper, Timothy M., Cheney, Daniel L., Luettgen, Joseph M., Wong, Pancras C., Seiffert, Dietmar, Wexler, Ruth R., and Priestley, E. Scott
- Published
- 2016
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13. Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure.
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Richter JM, Gunaga P, Yadav N, Bora RO, Bhide R, Rajugowda N, Govindrajulu K, Godesi S, Akuthota N, Rao P, Sivaraman A, Panda M, Kaspady M, Gupta A, Mathur A, Levesque PC, Gulia J, Dokania M, Ramarao M, Kole P, Chacko S, Lentz KA, Sivaprasad Lvj S, Thatipamula RP, Sridhar S, Kamble S, Govindrajan A, Soleman SI, Gordon DA, Wexler RR, and Priestley ES
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- Animals, Humans, Rats, Structure-Activity Relationship, Potassium Channels, Inwardly Rectifying antagonists & inhibitors, Potassium Channels, Inwardly Rectifying metabolism, Drug Discovery, Diuresis drug effects, Piperazines pharmacology, Piperazines chemistry, Piperazines therapeutic use, Piperazines chemical synthesis, Piperazines pharmacokinetics, Male, Rats, Sprague-Dawley, Heart Failure drug therapy, Potassium Channel Blockers therapeutic use, Potassium Channel Blockers pharmacology, Potassium Channel Blockers chemistry, Potassium Channel Blockers pharmacokinetics, Potassium Channel Blockers chemical synthesis
- Abstract
Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
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- 2024
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14. Empowering Voices: Inspiring Women in Medicinal Chemistry.
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Blanco MJ, Bronson JJ, DiMauro EF, Dzierba C, Eggen M, Garner AL, Georg G, Giarolla J, Goodwin NC, Grenier-Davies MC, Haskell-Luevano C, Holzgrabe U, Huang R, Lagiakos HR, Leftheris K, Martin Y, Matos MJ, May-Dracka TL, Müller CE, Newman AH, Parmee E, Petter JC, Tamayo NA, Wexler RR, Bolognesi ML, Ripka A, and Young W
- Subjects
- Humans, Female, Chemistry, Pharmaceutical, Power, Psychological
- Abstract
As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.
- Published
- 2024
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15. Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis.
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Zhang X, Jiang W, Richter JM, Bates JA, Reznik SK, Stachura S, Rampulla R, Doddalingappa D, Ulaganathan S, Hua J, Bostwick JS, Sum C, Posy S, Malmstrom S, Dickey J, Harden D, Lawrence RM, Guarino VR, Schumacher WA, Wong P, Yang J, Gordon DA, Wexler RR, and Priestley ES
- Subjects
- Animals, Macaca fascicularis, Quinoxalines pharmacology, Quinoxalines therapeutic use, Receptors, Thrombin, Thrombin, Hemorrhage, Receptor, PAR-1, Blood Platelets, Platelet Aggregation, Fibrinolytic Agents pharmacology, Fibrinolytic Agents therapeutic use, Thrombosis drug therapy, Thrombosis prevention & control
- Abstract
PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low μM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48 , possessing a 2 nM IC
50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.- Published
- 2024
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16. Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.
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Priestley ES, Banville J, Deon D, Dubé L, Gagnon M, Guy J, Lapointe P, Lavallée JF, Martel A, Plamondon S, Rémillard R, Ruediger E, Tremblay F, Posy SL, Guarino VR, Richter JM, Li J, Gupta A, Vetrichelvan M, Balapragalathan TJ, Mathur A, Hua J, Callejo M, Guay J, Sum CS, Cvijic ME, Watson C, Wong P, Yang J, Bouvier M, Gordon DA, Wexler RR, and Marinier A
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- Benzofurans, Blood Platelets, Humans, Imidazoles, Morpholines, Receptor, PAR-1, Receptors, Thrombin, Thiazoles, Thrombin, Platelet Aggregation, Thrombosis drug therapy
- Abstract
Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 ( 43 ), and a backup clinical candidate, BMS-986141 ( 49 ). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
- Published
- 2022
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17. Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.
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Dilger AK, Pabbisetty KB, Corte JR, De Lucca I, Fang T, Yang W, Pinto DJP, Wang Y, Zhu Y, Mathur A, Li J, Hou X, Smith D, Sun D, Zhang H, Krishnananthan S, Wu DR, Myers JE Jr, Sheriff S, Rossi KA, Chacko S, Zheng JJ, Galella MA, Ziemba T, Dierks EA, Bozarth JM, Wu Y, Crain E, Wong PC, Luettgen JM, Wexler RR, and Ewing WR
- Subjects
- Animals, Mice, Rabbits, Administration, Oral, Macaca fascicularis, Molecular Structure, Pyrazoles administration & dosage, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrazoles therapeutic use, Rats, Sprague-Dawley, Structure-Activity Relationship, Rats, Carotid Artery Thrombosis drug therapy, Factor XIa antagonists & inhibitors, Fibrinolytic Agents administration & dosage, Fibrinolytic Agents chemical synthesis, Fibrinolytic Agents pharmacokinetics, Fibrinolytic Agents therapeutic use, Pyrimidines administration & dosage, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines therapeutic use, Triazoles administration & dosage, Triazoles chemical synthesis, Triazoles pharmacokinetics, Triazoles therapeutic use
- Abstract
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian ( BMS-986177/JNJ-70033093 , 17 , FXIa K
i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.- Published
- 2022
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18. Identification of a Hydroxypyrimidinone Compound ( 21 ) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure.
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Meng W, Pi Z, Brigance R, Rossi KA, Schumacher WA, Bostwick JS, Gargalovic PS, Onorato JM, Luk CE, Generaux CN, Wang T, Wexler RR, and Finlay HJ
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- Animals, Dogs, Drug Discovery, Humans, Pyrimidinones chemistry, Pyrimidinones pharmacokinetics, Pyrimidinones therapeutic use, Rats, Structure-Activity Relationship, Apelin Receptors agonists, Heart Failure drug therapy, Pyrimidinones pharmacology
- Abstract
This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound 2 showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites in vitro . In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.
- Published
- 2021
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19. Identification of 6-Hydroxypyrimidin-4(1 H )-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists.
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Pi Z, Johnson JA, Meng W, Phillips M, Schumacher WA, Bostwick JS, Gargalovic PS, Onorato JM, Generaux CN, Wang T, He Y, Gordon DA, Wexler RR, and Finlay HJ
- Abstract
The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and other cardiovascular diseases. (Pyr
1 )apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr1 )apelin-13 increases cardiac output in preclinical models and humans. Recently we disclosed clinical lead BMS-986224 ( 1 ), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr1 )apelin-13 in an acute rat pressure-volume loop model. Herein we describe the structure-activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4(1 H )-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1 ., Competing Interests: The authors declare the following competing financial interest(s): The authors of this Letter were employees of Bristol Myers Squibb at the time of this research., (© 2021 American Chemical Society.)- Published
- 2021
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20. Discovery of a High Affinity, Orally Bioavailable Macrocyclic FXIa Inhibitor with Antithrombotic Activity in Preclinical Species.
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Yang W, Wang Y, Lai A, Clark CG, Corte JR, Fang T, Gilligan PJ, Jeon Y, Pabbisetty KB, Rampulla RA, Mathur A, Kaspady M, Neithnadka PR, Arumugam A, Raju S, Rossi KA, Myers JE Jr, Sheriff S, Lou Z, Zheng JJ, Chacko SA, Bozarth JM, Wu Y, Crain EJ, Wong PC, Seiffert DA, Luettgen JM, Lam PYS, Wexler RR, and Ewing WR
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- Administration, Oral, Animals, Biological Availability, Crystallography, X-Ray, Dogs, Drug Evaluation, Preclinical, Factor XIa chemistry, Factor XIa metabolism, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacokinetics, Humans, Hydrophobic and Hydrophilic Interactions, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacokinetics, Macrocyclic Compounds pharmacology, Models, Molecular, Rabbits, Structure-Activity Relationship, Factor XIa antagonists & inhibitors, Fibrinolytic Agents administration & dosage, Fibrinolytic Agents pharmacology
- Abstract
Oral factor XIa (FXIa) inhibitors may provide a promising new antithrombotic therapy with an improved benefit to bleeding risk profile over existing antithrombotic agents. Herein, we report application of a previously disclosed cyclic carbamate P1 linker which provided improved oral bioavailability in the imidazole-based 13-membered macrocycle to the 12-membered macrocycle. This resulted in identification of compound 4 with desired FXIa inhibitory potency and good oral bioavailability but high in vivo clearance. Further structure-activity relationship (SAR) studies of heterocyclic core modifications to replace the imidazole core as well as various linkers to the P1 group led to the discovery of compound 6f , a potent FXIa inhibitor with selectivity against most of the relevant serine proteases. Compound 6f also demonstrated excellent pharmacokinetics (PK) profile (high oral bioavailability and low clearance) in multiple preclinical species. Compound 6f achieved robust antithrombotic efficacy in a rabbit efficacy model at doses which preserved hemostasis.
- Published
- 2020
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21. Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo.
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Tora G, Kim SH, Pi Z, Johnson JA, Jiang J, Phillips M, Lloyd J, Abell LM, Lu H, Locke G, Adam LP, Taylor DS, Yin X, Behnia K, Zhao L, Yang R, Basso M, Caporuscio C, Chen AY, Liu E, Kirshgessner T, Onorato JM, Ryan C, Traeger SC, Gordon D, Wexler RR, and Finlay HJ
- Subjects
- Animals, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Ketones chemical synthesis, Ketones pharmacokinetics, Male, Mice, Inbred C57BL, Molecular Structure, Oxadiazoles chemical synthesis, Oxadiazoles pharmacokinetics, Structure-Activity Relationship, Cholesterol, HDL metabolism, Enzyme Inhibitors pharmacology, Ketones pharmacology, Lipase antagonists & inhibitors, Oxadiazoles pharmacology
- Abstract
Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12 . Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.
- Published
- 2020
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22. Potent, Orally Bioavailable, and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
- Author
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Corte JR, Pinto DJP, Fang T, Osuna H, Yang W, Wang Y, Lai A, Clark CG, Sun JH, Rampulla R, Mathur A, Kaspady M, Neithnadka PR, Li YC, Rossi KA, Myers JE Jr, Sheriff S, Lou Z, Harper TW, Huang C, Zheng JJ, Bozarth JM, Wu Y, Wong PC, Crain EJ, Seiffert DA, Luettgen JM, Lam PYS, Wexler RR, and Ewing WR
- Subjects
- Animals, Biological Availability, Blood Coagulation drug effects, Crystallography, X-Ray, Drug Design, Drug Discovery, Fibrinolytic Agents pharmacokinetics, Humans, Imidazoles chemical synthesis, Imidazoles pharmacology, Macrocyclic Compounds chemical synthesis, Macrocyclic Compounds pharmacology, Models, Molecular, Partial Thromboplastin Time, Rabbits, Serine Proteinase Inhibitors chemical synthesis, Serine Proteinase Inhibitors pharmacology, Structure-Activity Relationship, Thrombosis drug therapy, Factor XIa antagonists & inhibitors, Fibrinolytic Agents chemical synthesis, Fibrinolytic Agents pharmacology, Pyridines chemical synthesis, Pyridines pharmacology
- Abstract
Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19 , possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.
- Published
- 2020
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23. Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.
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Miller MM, Banville J, Friends TJ, Gagnon M, Hangeland JJ, Lavallée JF, Martel A, O'Grady H, Rémillard R, Ruediger E, Tremblay F, Posy SL, Allegretto NJ, Guarino VR, Harden DG, Harper TW, Hartl K, Josephs J, Malmstrom S, Watson C, Yang Y, Zhang G, Wong P, Yang J, Bouvier M, Seiffert DA, Wexler RR, Lawrence RM, Priestley ES, and Marinier A
- Subjects
- Animals, Benzofurans chemistry, Benzofurans pharmacokinetics, Biological Availability, Disease Models, Animal, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacokinetics, HEK293 Cells, Hemorrhage metabolism, Humans, Macaca fascicularis, Models, Chemical, Molecular Structure, Platelet Aggregation drug effects, Receptors, Thrombin genetics, Receptors, Thrombin metabolism, Structure-Activity Relationship, Thrombosis metabolism, Benzofurans pharmacology, Fibrinolytic Agents pharmacology, Hemorrhage prevention & control, Receptors, Thrombin antagonists & inhibitors, Thrombosis prevention & control
- Abstract
In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651 , in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651 . UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
- Published
- 2019
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24. Discovery of a Lead Triphenylethanamine Cholesterol Ester Transfer Protein (CETP) Inhibitor.
- Author
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Finlay HJ, Jiang J, Rampulla R, Salvati ME, Qiao JX, Wang TC, Lawrence RM, Harikrishnan LS, Kamau MG, Taylor DS, Chen AYA, Yin X, Huang CS, Chang M, Chen XQ, Sleph PG, Xu C, Li J, Levesque P, Adam LP, and Wexler RR
- Abstract
Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N -terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino- N -(( R )-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide ( 13 ). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters., Competing Interests: The authors declare no competing financial interest.
- Published
- 2019
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25. Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase.
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Johnson JA, Tora G, Pi Z, Phillips M, Yin X, Yang R, Zhao L, Chen AY, Taylor DS, Basso M, Rose A, Behnia K, Onorato J, Chen XQ, Abell LM, Lu H, Locke G, Caporuscio C, Galella M, Adam LP, Gordon D, Wexler RR, and Finlay HJ
- Abstract
Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24 , which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
- Full Text
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26. Potent Triazolopyridine Myeloperoxidase Inhibitors.
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Wurtz NR, Viet A, Shaw SA, Dilger A, Valente MN, Khan JA, Jusuf S, Narayanan R, Fernando G, Lo F, Liu X, Locke GA, Kopcho L, Abell LM, Sleph P, Basso M, Zhao L, Wexler RR, Duclos F, and Kick EK
- Abstract
Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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27. PK/PD Disconnect Observed with a Reversible Endothelial Lipase Inhibitor.
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Hangeland JJ, Abell LM, Adam LP, Jiang J, Friends TJ, Haque LE, Neels J, Onorato JM, Chen AYA, Taylor DS, Yin X, Harrity TW, Basso MD, Yang R, Sleph PG, Gordon DA, Huang CS, Wexler RR, Finlay HJ, and Lawrence RM
- Abstract
Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N -(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide ( 5 ; EL IC
50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N -(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1 H -pyrrole-3-carboxamide ( 6a ; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N -(4-(3,4 - dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1 H -pyrrole-3-carboxamide ( 7c ; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a , providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation., Competing Interests: The authors declare no competing financial interest.- Published
- 2018
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- View/download PDF
28. Correction to "Atropisomer Control in Macrocyclic Factor VIIa Inhibitors".
- Author
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Glunz PW, Mueller L, Cheney DL, Ladziata V, Zou Y, Wurtz NR, Wei A, Wong PC, Wexler RR, and Priestley ES
- Published
- 2018
- Full Text
- View/download PDF
29. Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212).
- Author
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Pinto DJP, Orwat MJ, Smith LM 2nd, Quan ML, Lam PYS, Rossi KA, Apedo A, Bozarth JM, Wu Y, Zheng JJ, Xin B, Toussaint N, Stetsko P, Gudmundsson O, Maxwell B, Crain EJ, Wong PC, Lou Z, Harper TW, Chacko SA, Myers JE Jr, Sheriff S, Zhang H, Hou X, Mathur A, Seiffert DA, Wexler RR, Luettgen JM, and Ewing WR
- Subjects
- Animals, Anticoagulants pharmacokinetics, Anticoagulants pharmacology, Blood Coagulation drug effects, Crystallography, X-Ray, Dogs, Drug Discovery, Factor XIa chemistry, Factor XIa metabolism, Humans, Isoquinolines pharmacokinetics, Isoquinolines pharmacology, Male, Molecular Docking Simulation, Rabbits, Rats, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacokinetics, Small Molecule Libraries pharmacology, Small Molecule Libraries therapeutic use, Thrombosis blood, para-Aminobenzoates pharmacokinetics, para-Aminobenzoates pharmacology, Anticoagulants chemistry, Anticoagulants therapeutic use, Factor XIa antagonists & inhibitors, Isoquinolines chemistry, Isoquinolines therapeutic use, Thrombosis drug therapy, para-Aminobenzoates chemistry, para-Aminobenzoates therapeutic use
- Abstract
Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K
i = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.- Published
- 2017
- Full Text
- View/download PDF
30. Selective I Kur Inhibitors for the Potential Treatment of Atrial Fibrillation: Optimization of the Phenyl Quinazoline Series Leading to Clinical Candidate 5-[5-Phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide.
- Author
-
Gunaga P, Lloyd J, Mummadi S, Banerjee A, Dhondi NK, Hennan J, Subray V, Jayaram R, Rajugowda N, Umamaheshwar Reddy K, Kumaraguru D, Mandal U, Beldona D, Adisechen AK, Yadav N, Warrier J, Johnson JA, Sale H, Putlur SP, Saxena A, Chimalakonda A, Mandlekar S, Conder M, Xing D, Gupta AK, Gupta A, Rampulla R, Mathur A, Levesque P, Wexler RR, and Finlay HJ
- Subjects
- Animals, Carbon-13 Magnetic Resonance Spectroscopy, Dogs, Mass Spectrometry, Potassium Channel Blockers pharmacology, Proton Magnetic Resonance Spectroscopy, Quinazolines chemistry, Quinazolines pharmacology, Rabbits, Sodium Channel Blockers pharmacology, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Atrial Fibrillation drug therapy, Potassium Channel Blockers therapeutic use, Quinazolines therapeutic use, Sodium Channel Blockers therapeutic use, Sulfonamides therapeutic use
- Abstract
We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent I
Kur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.- Published
- 2017
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- View/download PDF
31. Design and Synthesis of Novel Meta-Linked Phenylglycine Macrocyclic FVIIa Inhibitors.
- Author
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Richter JM, Cheney DL, Bates JA, Wei A, Luettgen JM, Rendina AR, Harper TM, Narayanan R, Wong PC, Seiffert D, Wexler RR, and Priestley ES
- Abstract
Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa K
i was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.- Published
- 2016
- Full Text
- View/download PDF
32. Discovery of Highly Potent Liver X Receptor β Agonists.
- Author
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Kick EK, Busch BB, Martin R, Stevens WC, Bollu V, Xie Y, Boren BC, Nyman MC, Nanao MH, Nguyen L, Plonowski A, Schulman IG, Yan G, Zhang H, Hou X, Valente MN, Narayanan R, Behnia K, Rodrigues AD, Brock B, Smalley J, Cantor GH, Lupisella J, Sleph P, Grimm D, Ostrowski J, Wexler RR, Kirchgessner T, and Mohan R
- Abstract
Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15 . The addition of polarity to the phenyl sulfone also reduced binding to the plasma protein, human α-1-acid glycoprotein. Agonist 15 was selected for clinical development based on the favorable combination of in vitro properties, excellent pharmacokinetic parameters, and a favorable lipid profile.
- Published
- 2016
- Full Text
- View/download PDF
33. Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors.
- Author
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Wurtz NR, Parkhurst BL, Jiang W, DeLucca I, Zhang X, Ladziata V, Cheney DL, Bozarth JR, Rendina AR, Wei A, Luettgen JM, Wu Y, Wong PC, Seiffert DA, Wexler RR, and Priestley ES
- Abstract
Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2 H )-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.
- Published
- 2016
- Full Text
- View/download PDF
34. Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex.
- Author
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Zhang X, Glunz PW, Johnson JA, Jiang W, Jacutin-Porte S, Ladziata V, Zou Y, Phillips MS, Wurtz NR, Parkhurst B, Rendina AR, Harper TM, Cheney DL, Luettgen JM, Wong PC, Seiffert D, Wexler RR, and Priestley ES
- Subjects
- Administration, Oral, Animals, Anticoagulants administration & dosage, Anticoagulants chemistry, Biological Availability, Dogs, Dose-Response Relationship, Drug, Factor VIIa metabolism, Healthy Volunteers, Humans, Macrocyclic Compounds administration & dosage, Macrocyclic Compounds chemistry, Male, Models, Molecular, Molecular Structure, Rabbits, Structure-Activity Relationship, Thromboplastin metabolism, Anticoagulants pharmacology, Drug Discovery, Factor VIIa antagonists & inhibitors, Macrocyclic Compounds pharmacology, Thromboplastin antagonists & inhibitors
- Abstract
Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.
- Published
- 2016
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- View/download PDF
35. Discovery of 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine as a Potent I Kur Inhibitor.
- Author
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Finlay HJ, Johnson JA, Lloyd JL, Jiang J, Neels J, Gunaga P, Banerjee A, Dhondi N, Chimalakonda A, Mandlekar S, Conder ML, Sale H, Xing D, Levesque P, and Wexler RR
- Abstract
A new series of phenylquinazoline inhibitors of Kv 1.5 is disclosed. The series was optimized for Kv 1.5 potency, selectivity versus hERG, pharmacokinetic exposure, and pharmacodynamic potency. 5-Phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine (13k) was identified as a potent and ion channel selective inhibitor with robust efficacy in the preclinical rat ventricular effective refractory period (VERP) model and the rabbit atrial effective refractory period (AERP) model.
- Published
- 2016
- Full Text
- View/download PDF
36. Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of N-[(1R)-1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)benzamide (BMS-795311).
- Author
-
Qiao JX, Wang TC, Adam LP, Chen AY, Taylor DS, Yang RZ, Zhuang S, Sleph PG, Li JP, Li D, Yin X, Chang M, Chen XQ, Shen H, Li J, Smith D, Wu DR, Leith L, Harikrishnan LS, Kamau MG, Miller MM, Bilder D, Rampulla R, Li YX, Xu C, Lawrence RM, Poss MA, Levesque P, Gordon DA, Huang CS, Finlay HJ, Wexler RR, and Salvati ME
- Subjects
- Animals, Anticholesteremic Agents pharmacokinetics, Atherosclerosis drug therapy, Benzamides pharmacokinetics, Benzylamines pharmacokinetics, Blood Pressure drug effects, Cell Line, Cholesterol metabolism, Cholesterol, HDL blood, Cricetinae, Cytochrome P-450 CYP11B2 antagonists & inhibitors, Dogs, Drug Discovery, Humans, Macaca fascicularis, Male, Mesocricetus, Mice, Mice, Transgenic, Motor Activity drug effects, Quinolines pharmacology, Rats, Rats, Sprague-Dawley, Anticholesteremic Agents chemical synthesis, Anticholesteremic Agents pharmacology, Benzamides chemical synthesis, Benzamides pharmacology, Benzylamines chemical synthesis, Benzylamines pharmacology, Cholesterol Ester Transfer Proteins antagonists & inhibitors
- Abstract
Cholesteryl ester transfer protein (CETP) inhibitors raise HDL-C in animals and humans and may be antiatherosclerotic by enhancing reverse cholesterol transport (RCT). In this article, we describe the lead optimization efforts resulting in the discovery of a series of triphenylethanamine (TPE) ureas and amides as potent and orally available CETP inhibitors. Compound 10g is a potent CETP inhibitor that maximally inhibited cholesteryl ester (CE) transfer activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic mice and increased HDL cholesterol content and size comparable to torcetrapib (1) in moderately-fat fed hamsters. In contrast to the off-target liabilities with 1, no blood pressure increase was observed with 10g in rat telemetry studies and no increase of aldosterone synthase (CYP11B2) was detected in H295R cells. On the basis of its preclinical profile, compound 10g was advanced into preclinical safety studies.
- Published
- 2015
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- View/download PDF
37. Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors.
- Author
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Priestley ES, Cheney DL, DeLucca I, Wei A, Luettgen JM, Rendina AR, Wong PC, and Wexler RR
- Subjects
- Drug Design, Macrocyclic Compounds chemistry, Macrocyclic Compounds pharmacology, Models, Molecular, Molecular Structure, Factor VIIa antagonists & inhibitors, Serine Proteinase Inhibitors chemistry, Serine Proteinase Inhibitors pharmacology
- Abstract
On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.
- Published
- 2015
- Full Text
- View/download PDF
38. Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.
- Author
-
Hu Z, Wong PC, Gilligan PJ, Han W, Pabbisetty KB, Bozarth JM, Crain EJ, Harper T, Luettgen JM, Myers JE Jr, Ramamurthy V, Rossi KA, Sheriff S, Watson CA, Wei A, Zheng JJ, Seiffert DA, Wexler RR, and Quan ML
- Abstract
Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.
- Published
- 2015
- Full Text
- View/download PDF
39. Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening.
- Author
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Cheney DL, Bozarth JM, Metzler WJ, Morin PE, Mueller L, Newitt JA, Nirschl AH, Rendina AR, Tamura JK, Wei A, Wen X, Wurtz NR, Seiffert DA, Wexler RR, and Priestley ES
- Subjects
- Blood Coagulation drug effects, Crystallography, X-Ray, Factor VIIa metabolism, Halogens chemistry, Halogens pharmacology, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Humans, Lactams metabolism, Lactams pharmacology, Models, Molecular, Molecular Docking Simulation, Drug Design, Factor VIIa antagonists & inhibitors, Serine Proteinase Inhibitors chemistry, Serine Proteinase Inhibitors pharmacology
- Abstract
A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
- Published
- 2015
- Full Text
- View/download PDF
40. Phenylimidazoles as potent and selective inhibitors of coagulation factor XIa with in vivo antithrombotic activity.
- Author
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Hangeland JJ, Friends TJ, Rossi KA, Smallheer JM, Wang C, Sun Z, Corte JR, Fang T, Wong PC, Rendina AR, Barbera FA, Bozarth JM, Luettgen JM, Watson CA, Zhang G, Wei A, Ramamurthy V, Morin PE, Bisacchi GS, Subramaniam S, Arunachalam P, Mathur A, Seiffert DA, Wexler RR, and Quan ML
- Subjects
- Animals, Crystallography, X-Ray, Fibrinolytic Agents pharmacokinetics, Fibrinolytic Agents pharmacology, Humans, Imidazoles pharmacokinetics, Imidazoles pharmacology, Indazoles pharmacokinetics, Indazoles pharmacology, Models, Molecular, Partial Thromboplastin Time, Rabbits, Thrombosis prevention & control, Fibrinolytic Agents chemical synthesis, Imidazoles chemical synthesis, Indazoles chemical synthesis
- Abstract
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
- Published
- 2014
- Full Text
- View/download PDF
41. Discovery of 4-aryl-7-hydroxyindoline-based P2Y1 antagonists as novel antiplatelet agents.
- Author
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Yang W, Wang Y, Lai A, Qiao JX, Wang TC, Hua J, Price LA, Shen H, Chen XQ, Wong P, Crain E, Watson C, Huang CS, Seiffert DA, Rehfuss R, Wexler RR, and Lam PY
- Subjects
- Animals, Blood Coagulation drug effects, Dose-Response Relationship, Drug, Humans, Indoles chemistry, Mice, Microsomes, Liver chemistry, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Molecular Structure, Platelet Aggregation drug effects, Platelet Aggregation Inhibitors chemical synthesis, Platelet Aggregation Inhibitors chemistry, Purinergic P2Y Receptor Antagonists chemical synthesis, Purinergic P2Y Receptor Antagonists chemistry, Rabbits, Rats, Structure-Activity Relationship, Thrombosis drug therapy, Drug Discovery, Indoles pharmacology, Platelet Aggregation Inhibitors pharmacology, Purinergic P2Y Receptor Antagonists pharmacology, Receptors, Purinergic P2Y1 metabolism
- Abstract
Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.
- Published
- 2014
- Full Text
- View/download PDF
42. Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors.
- Author
-
Quan ML, Wong PC, Wang C, Woerner F, Smallheer JM, Barbera FA, Bozarth JM, Brown RL, Harpel MR, Luettgen JM, Morin PE, Peterson T, Ramamurthy V, Rendina AR, Rossi KA, Watson CA, Wei A, Zhang G, Seiffert D, and Wexler RR
- Subjects
- Animals, Bleeding Time, Crystallography, X-Ray, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, Humans, Molecular Conformation, Molecular Docking Simulation, Quinolines chemistry, Quinolines pharmacology, Rabbits, Stereoisomerism, Structure-Activity Relationship, Factor Xa Inhibitors, Fibrinolytic Agents chemical synthesis, Quinolines chemical synthesis
- Abstract
Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.
- Published
- 2014
- Full Text
- View/download PDF
43. Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors.
- Author
-
Zhang X, Jiang W, Jacutin-Porte S, Glunz PW, Zou Y, Cheng X, Nirschl AH, Wurtz NR, Luettgen JM, Rendina AR, Luo G, Harper TM, Wei A, Anumula R, Cheney DL, Knabb RM, Wong PC, Wexler RR, and Priestley ES
- Abstract
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t 1/2 in dog PK studies.
- Published
- 2013
- Full Text
- View/download PDF
44. Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist.
- Author
-
Qiao JX, Wang TC, Ruel R, Thibeault C, L'Heureux A, Schumacher WA, Spronk SA, Hiebert S, Bouthillier G, Lloyd J, Pi Z, Schnur DM, Abell LM, Hua J, Price LA, Liu E, Wu Q, Steinbacher TE, Bostwick JS, Chang M, Zheng J, Gao Q, Ma B, McDonnell PA, Huang CS, Rehfuss R, Wexler RR, and Lam PY
- Subjects
- Animals, Biological Availability, Humans, Indoles chemistry, Models, Molecular, Phenylurea Compounds chemistry, Phenylurea Compounds metabolism, Purinergic P2Y Receptor Antagonists chemistry, Purinergic P2Y Receptor Antagonists metabolism, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2Y1 chemistry, Sequence Homology, Amino Acid, Spiro Compounds chemistry, Spiro Compounds metabolism, Urea chemistry, Urea metabolism, Drug Design, Molecular Conformation, Phenylurea Compounds pharmacokinetics, Phenylurea Compounds pharmacology, Purinergic P2Y Receptor Antagonists pharmacokinetics, Purinergic P2Y Receptor Antagonists pharmacology, Receptors, Purinergic P2Y1 metabolism, Spiro Compounds pharmacokinetics, Spiro Compounds pharmacology, Urea pharmacokinetics, Urea pharmacology
- Abstract
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
- Published
- 2013
- Full Text
- View/download PDF
45. Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y1 antagonists.
- Author
-
Chao H, Turdi H, Herpin TF, Roberge JY, Liu Y, Schnur DM, Poss MA, Rehfuss R, Hua J, Wu Q, Price LA, Abell LM, Schumacher WA, Bostwick JS, Steinbacher TE, Stewart AB, Ogletree ML, Huang CS, Chang M, Cacace AM, Arcuri MJ, Celani D, Wexler RR, and Lawrence RM
- Subjects
- Animals, Arterial Occlusive Diseases blood, Arterial Occlusive Diseases drug therapy, Bleeding Time, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, HEK293 Cells, Humans, Male, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacology, Platelet Aggregation drug effects, Purinergic P2Y Receptor Antagonists chemistry, Purinergic P2Y Receptor Antagonists pharmacology, Pyridines chemistry, Pyridines pharmacology, Rats, Structure-Activity Relationship, Thrombosis blood, Thrombosis drug therapy, Urea chemical synthesis, Urea chemistry, Urea pharmacology, Fibrinolytic Agents chemical synthesis, Phenylurea Compounds chemical synthesis, Purinergic P2Y Receptor Antagonists chemical synthesis, Pyridines chemical synthesis, Urea analogs & derivatives
- Abstract
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP-mediated platelet aggregation in human blood samples is described. Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 ± 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y1 antagonist could potentially provide a safe and efficacious antithrombotic profile.
- Published
- 2013
- Full Text
- View/download PDF
46. Diphenylpyridylethanamine (DPPE) derivatives as cholesteryl ester transfer protein (CETP) inhibitors.
- Author
-
Harikrishnan LS, Finlay HJ, Qiao JX, Kamau MG, Jiang J, Wang TC, Li J, Cooper CB, Poss MA, Adam LP, Taylor DS, Chen AY, Yin X, Sleph PG, Yang RZ, Sitkoff DF, Galella MA, Nirschl DS, Van Kirk K, Miller AV, Huang CS, Chang M, Chen XQ, Salvati ME, Wexler RR, and Lawrence RM
- Subjects
- Animals, Anticholesteremic Agents chemical synthesis, Apolipoprotein B-100 antagonists & inhibitors, Apolipoprotein B-100 metabolism, Blood Pressure drug effects, Cholesterol Ester Transfer Proteins metabolism, Coronary Disease drug therapy, Cricetinae, Drug Discovery, Heart Rate drug effects, Humans, Inhibitory Concentration 50, Male, Mice, Mice, Transgenic, Molecular Structure, Pyridines chemical synthesis, Rats, Stilbenes chemical synthesis, Anticholesteremic Agents chemistry, Anticholesteremic Agents pharmacology, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Pyridines chemistry, Pyridines pharmacology, Stilbenes chemistry, Stilbenes pharmacology
- Abstract
A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.
- Published
- 2012
- Full Text
- View/download PDF
47. Transformation of anionically activated trifluoromethyl groups to heterocycles under mild aqueous conditions.
- Author
-
Qiao JX, Wang TC, Hu C, Li J, Wexler RR, and Lam PY
- Subjects
- Anions chemistry, Methylation, Molecular Structure, Stereoisomerism, Fluorine Compounds chemistry, Heterocyclic Compounds chemistry
- Abstract
The (hetero)aromatic trifluoromethyl group is present in many biologically active molecules and is generally considered to be chemically stable. In this paper, a convenient one-step synthesis of C-C linked aryl-heterocycles or heteroaryl-heterocycles in good to excellent yields via the reaction of anionically activated trifluoromethyl groups with amino nucleophiles containing a second NH, OH, or SH nucleophile in 1 N sodium hydroxide is reported. The method has high functional group tolerability and is potentially useful in parallel synthesis.
- Published
- 2011
- Full Text
- View/download PDF
48. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.
- Author
-
Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, Smallwood A, Wong PC, Rendina AR, Luettgen JM, Knabb RM, He K, Xin B, Wexler RR, and Lam PY
- Subjects
- Administration, Oral, Animals, Biological Availability, Blood Coagulation drug effects, Crystallography, X-Ray, Dogs, Fibrinolytic Agents pharmacokinetics, Fibrinolytic Agents pharmacology, Humans, In Vitro Techniques, Models, Molecular, Molecular Structure, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyridones pharmacokinetics, Pyridones pharmacology, Rabbits, Structure-Activity Relationship, Factor Xa Inhibitors, Fibrinolytic Agents chemical synthesis, Pyrazoles chemical synthesis, Pyridones chemical synthesis
- Abstract
Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
- Published
- 2007
- Full Text
- View/download PDF
49. Discovery of 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent, selective, and orally bioavailable factor Xa inhibitor.
- Author
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Quan ML, Lam PY, Han Q, Pinto DJ, He MY, Li R, Ellis CD, Clark CG, Teleha CA, Sun JH, Alexander RS, Bai S, Luettgen JM, Knabb RM, Wong PC, and Wexler RR
- Subjects
- Administration, Oral, Animals, Biological Availability, Blood Proteins metabolism, Caco-2 Cells, Crystallography, X-Ray, Dogs, Fibrinolytic Agents chemistry, Fibrinolytic Agents pharmacology, Humans, Imidazoles chemistry, Imidazoles pharmacology, Isoxazoles chemistry, Isoxazoles pharmacology, Models, Molecular, Permeability, Protein Binding, Pyrazoles chemistry, Pyrazoles pharmacology, Rabbits, Structure-Activity Relationship, Thrombosis prevention & control, Factor Xa Inhibitors, Fibrinolytic Agents chemical synthesis, Imidazoles chemical synthesis, Isoxazoles chemical synthesis, Pyrazoles chemical synthesis
- Abstract
Modification of a series of pyrazole factor Xa inhibitors to incorporate an aminobenzisoxazole as the P(1) ligand resulted in compounds with improved selectivity for factor Xa relative to trypsin and plasma kallikrein. Further optimization of the P(4) moiety led to compounds with enhanced permeability and reduced protein binding. The SAR and pharmacokinetic profile of this series of compounds is described herein. These efforts culminated in 1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-N-[2-fluoro-4-[(2'-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide (11d), a potent, selective, and orally bioavailable inhibitor of factor Xa. On the basis of its excellent in vitro potency and selectivity profile, high free fraction in human plasma, good oral bioavailability, and in vivo efficacy in antithrombotic models, the HCl salt of this compound was selected for clinical development as razaxaban (DPC 906, BMS-561389).
- Published
- 2005
- Full Text
- View/download PDF
50. Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1).
- Author
-
Pruitt JR, Pinto DJ, Galemmo RA Jr, Alexander RS, Rossi KA, Wells BL, Drummond S, Bostrom LL, Burdick D, Bruckner R, Chen H, Smallwood A, Wong PC, Wright MR, Bai S, Luettgen JM, Knabb RM, Lam PY, and Wexler RR
- Subjects
- Administration, Oral, Animals, Arteriovenous Shunt, Surgical, Biological Availability, Crystallography, X-Ray, Dogs, Factor Xa chemistry, Humans, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Rabbits, Structure-Activity Relationship, Thrombosis prevention & control, Factor Xa Inhibitors, Pyrazoles chemical synthesis
- Abstract
Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.
- Published
- 2003
- Full Text
- View/download PDF
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