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Your search keyword '"Wexler, Ruth R."' showing total 19 results
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19 results on '"Wexler, Ruth R."'

2. Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists.

Author

Wurtz, Nicholas R., Shirude, Pravin S., Cheney, Daniel L, Lupisella, John A., Chattopadhyay, Amit Kumar, Baligar, Vishweshwaraiah, Seshadri, Balaji, Anjanappa, Prakash, Viet, Andrew, Valente, Meriah N., Hsu, Mei-Yin, Abousleiman, Mojgan, Sarodaya, Sanket, Tagore, Debarati M., Dudhgaonkar, Shailesh, Putlur, Sivaprasad, Dierks, Elizabeth A., Ostrowski, Jacek, Wexler, Ruth R., and Garcia, Ricardo

Published
2024
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3. Discovery of BMS-986308: A Renal Outer Medullary Potassium Channel Inhibitor for the Treatment of Heart Failure

Author

Richter, Jeremy M., Gunaga, Prashantha, Yadav, Navnath, Bora, Rajesh Onkardas, Bhide, Rajeev, Rajugowda, Nagendra, Govindrajulu, Kavitha, Godesi, Sreenivasulu, Akuthota, Nagarjuna, Rao, Prasanna, Sivaraman, Aneesh, Panda, Manoranjan, Kaspady, Mahammed, Gupta, Anuradha, Mathur, Arvind, Levesque, Paul C., Gulia, Jyoti, Dokania, Manoj, Ramarao, Manjunath, Kole, Prashant, Chacko, Silvi, Lentz, Kimberley A., Sivaprasad LVJ, Sankara, Thatipamula, Rajendra Prasad, Sridhar, Srikanth, Kamble, Shyam, Govindrajan, Arun, Soleman, Sharif I., Gordon, David A., Wexler, Ruth R., and Priestley, E. Scott

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.

Published
2024
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6. Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4

Author

Priestley, E. Scott, primary, Banville, Jacques, additional, Deon, Daniel, additional, Dubé, Laurence, additional, Gagnon, Marc, additional, Guy, Julia, additional, Lapointe, Philippe, additional, Lavallée, Jean-François, additional, Martel, Alain, additional, Plamondon, Serge, additional, Rémillard, Roger, additional, Ruediger, Edward, additional, Tremblay, François, additional, Posy, Shana L., additional, Guarino, Victor R., additional, Richter, Jeremy M., additional, Li, Jianqing, additional, Gupta, Anuradha, additional, Vetrichelvan, Muthalagu, additional, Balapragalathan, T. J., additional, Mathur, Arvind, additional, Hua, Ji, additional, Callejo, Mario, additional, Guay, Jocelyne, additional, Sum, Chi Shing, additional, Cvijic, Mary Ellen, additional, Watson, Carol, additional, Wong, Pancras, additional, Yang, Jing, additional, Bouvier, Michel, additional, Gordon, David A., additional, Wexler, Ruth R., additional, and Marinier, Anne, additional

Published
2022
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7. Discovery of Heteroaryl Urea Isosteres for Formyl Peptide Receptor 2 Agonists

Author

Wurtz, Nicholas R., primary, Johnson, James A., additional, Viet, Andrew, additional, Shirude, Pravin S., additional, Baligar, Vishweshwaraiah, additional, Madduri, Sudhakara, additional, Cheney, Daniel L., additional, Park, Hyunsoo, additional, Lupisella, John A., additional, Hsu, Mei-Yin, additional, Abousleiman, Mojgan, additional, Galella, Michael A., additional, Aulakh, Darpandeep, additional, Dierks, Elizabeth A., additional, Garcia, Ricardo A., additional, Ostrowski, Jacek, additional, Kick, Ellen K., additional, and Wexler, Ruth R., additional

Published
2022
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8. Identification of a Hydroxypyrimidinone Compound (21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure

Author

Meng, Wei, primary, Pi, Zulan, additional, Brigance, Robert, additional, Rossi, Karen A., additional, Schumacher, William A., additional, Bostwick, Jeffrey S., additional, Gargalovic, Peter S., additional, Onorato, Joelle M., additional, Luk, Chiuwa E., additional, Generaux, Claudia N., additional, Wang, Tao, additional, Wexler, Ruth R., additional, and Finlay, Heather J., additional

Published
2021
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10. Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists

Author

Pi, Zulan, primary, Johnson, James A., additional, Meng, Wei, additional, Phillips, Monique, additional, Schumacher, William A., additional, Bostwick, Jeffrey S., additional, Gargalovic, Peter S., additional, Onorato, Joelle M., additional, Generaux, Claudia N., additional, Wang, Tao, additional, He, Yan, additional, Gordon, David A., additional, Wexler, Ruth R., additional, and Finlay, Heather J., additional

Published
2021
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14. Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis

Author

Zhang, Xiaojun, Jiang, Wen, Richter, Jeremy M., Bates, J. Alex, Reznik, Samuel K., Stachura, Sylwia, Rampulla, Richard, Doddalingappa, Dyamanna, Ulaganathan, Sankar, Hua, Ji, Bostwick, Jeffrey S., Sum, Chi, Posy, Shana, Malmstrom, Sarah, Dickey, Joyce, Harden, David, Lawrence, R. Michael, Guarino, Victor R., Schumacher, William A., Wong, Pancras, Yang, Jing, Gordon, David A., Wexler, Ruth R., and Priestley, E. Scott

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 3with 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 IC50against 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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15. Empowering Voices: Inspiring Women in Medicinal Chemistry

Author

Blanco, Maria-Jesus, Bronson, Joanne J., DiMauro, Erin F., Dzierba, Carolyn, Eggen, MariJean, Garner, Amanda L., Georg, Gunda, Giarolla, Jeanine, Goodwin, Nicole C., Grenier-Davies, Melissa C., Haskell-Luevano, Carrie, Holzgrabe, Ulrike, Huang, Rong, Lagiakos, H. Rachel, Leftheris, Katerina, Martin, Yvonne, Matos, Maria João, May-Dracka, Tricia L., Müller, Christa E., Newman, Amy H., Parmee, Emma, Petter, Jennifer C., Tamayo, Nuria A., Wexler, Ruth R., Bolognesi, Maria Laura, Ripka, Amy, and Young, Wendy

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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16. Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)

Author

Pinto, Donald J. P., Orwat, Michael J., Smith, Leon M., Quan, Mimi L., Lam, Patrick Y. S., Rossi, Karen A., Apedo, Atsu, Bozarth, Jeffrey M., Wu, Yiming, Zheng, Joanna J., Xin, Baomin, Toussaint, Nathalie, Stetsko, Paul, Gudmundsson, Olafur, Maxwell, Brad, Crain, Earl J., Wong, Pancras C., Lou, Zhen, Harper, Timothy W., Chacko, Silvi A., Myers, Joseph E., Sheriff, Steven, Zhang, Huiping, Hou, Xiaoping, Mathur, Arvind, Seiffert, Dietmar A., Wexler, Ruth R., Luettgen, Joseph M., and Ewing, William R.

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 Ki= 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
2024
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17. Empowering Voices: Inspiring Women in Medicinal Chemistry.

Author

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

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 by American Chemical Society.)

Published
2024
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18. Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

Author

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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19. Identification of 6-Hydroxypyrimidin-4(1 H )-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists.

Author

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 (Pyr 1 )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 (Pyr 1 )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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