12 results on '"Yan, Youwei"'
Search Results
2. Omarigliptin (MK-3102): ANovel Long-Acting DPP-4Inhibitor for Once-Weekly Treatment of Type 2 Diabetes.
- Author
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Biftu, Tesfaye, Sinha-Roy, Ranabir, Chen, Ping, Qian, Xiaoxia, Feng, Dennis, Kuethe, Jeffrey T., Scapin, Giovanna, Gao, Ying Duo, Yan, Youwei, Krueger, Davida, Bak, Annette, Eiermann, George, He, Jiafang, Cox, Jason, Hicks, Jacqueline, Lyons, Kathy, He, Huaibing, Salituro, Gino, Tong, Sharon, and Patel, Sangita
- Published
- 2014
- Full Text
- View/download PDF
3. Effects of Internal Stress and Hydrogen Penetration on the Performance of Er 2 O 3 Coatings as Hydrogen Permeation Barriers.
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Zheng Z, Yang Z, Yan Y, Wang X, and Li H
- Abstract
Ceramic coatings that can effectively prevent hydrogen permeation have a wide range of applications in hydrogen energy and nuclear fusion reactors. In this study, for the first time, the internal stress of Er
2 O3 coatings was found to be a key factor that could determine their hydrogen permeation resistance and lifespan. The internal stress was controlled by designing layered Er2 O3 coatings. The internal stress increased with an increasing number of Er2 O3 layers. When the number of layers was below 15, the increased internal stress did not adversely affect the coating performance and might help to increase its hydrogen permeation resistance. Although the overall thickness of the 15-layer Er2 O3 coating was only 97 nm, its hydrogen permeation reduction factor (PRF) reached the highest value of 626, whereas a further increase in the internal stress detrimentally affected the ability of the coating to reduce hydrogen permeation. In addition, the experimental observations and simulation results revealed that the performance of the Er2 O3 coatings was related to the hydrogen atoms that penetrated the coating, which weakened the Er-O bonds and consequently decreased the Er2 O3 fracture limit. This study provides insights into the effects of internal stress and hydrogen penetration on the performance of ceramic coatings as hydrogen permeation barriers and will help guide strategies for the structure design of hydrogen permeation barriers possessing high PRFs and long lifespans.- Published
- 2024
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4. Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.
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Ellis JM, Altman MD, Cash B, Haidle AM, Kubiak RL, Maddess ML, Yan Y, and Northrup AB
- Abstract
Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.
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- 2016
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5. Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
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Shipe WD, Sharik SS, Barrow JC, McGaughey GB, Theberge CR, Uslaner JM, Yan Y, Renger JJ, Smith SM, Coleman PJ, and Cox CD
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- Animals, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Disease Models, Animal, Dizocilpine Maleate pharmacology, Drug Discovery, Drug Evaluation, Preclinical methods, Humans, Male, Phosphodiesterase Inhibitors chemical synthesis, Phosphoric Diester Hydrolases chemistry, Phosphoric Diester Hydrolases metabolism, Pyrimidines chemistry, Rats, Wistar, Schizophrenia drug therapy, Phosphodiesterase Inhibitors chemistry, Phosphodiesterase Inhibitors pharmacology, Structure-Activity Relationship
- Abstract
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
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- 2015
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6. Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.
- Author
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Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, Scapin G, Gao YD, Yan Y, Krueger D, Bak A, Eiermann G, He J, Cox J, Hicks J, Lyons K, He H, Salituro G, Tong S, Patel S, Doss G, Petrov A, Wu J, Xu SS, Sewall C, Zhang X, Zhang B, Thornberry NA, and Weber AE
- Subjects
- Animals, Dipeptidyl-Peptidase IV Inhibitors chemical synthesis, Dipeptidyl-Peptidase IV Inhibitors pharmacokinetics, Dipeptidyl-Peptidase IV Inhibitors toxicity, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacokinetics, Heterocyclic Compounds, 2-Ring toxicity, Humans, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents toxicity, Pyrans chemical synthesis, Pyrans pharmacokinetics, Pyrans toxicity, Structure-Activity Relationship, Diabetes Mellitus, Type 2 drug therapy, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Heterocyclic Compounds, 2-Ring pharmacology, Hypoglycemic Agents pharmacology, Pyrans pharmacology
- Abstract
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
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- 2014
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7. Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase.
- Author
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Gomez R, Jolly SJ, Williams T, Vacca JP, Torrent M, McGaughey G, Lai MT, Felock P, Munshi V, Distefano D, Flynn J, Miller M, Yan Y, Reid J, Sanchez R, Liang Y, Paton B, Wan BL, and Anthony N
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- Animals, Anti-HIV Agents pharmacokinetics, Anti-HIV Agents pharmacology, Cells, Cultured, Dogs, HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-1 genetics, HIV-1 isolation & purification, Humans, Imidazoles pharmacokinetics, Imidazoles pharmacology, Indazoles pharmacokinetics, Indazoles pharmacology, Models, Molecular, Molecular Conformation, Mutation, Nitriles chemical synthesis, Nitriles pharmacokinetics, Nitriles pharmacology, Nitrobenzenes chemical synthesis, Nitrobenzenes pharmacokinetics, Nitrobenzenes pharmacology, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Rats, Rats, Sprague-Dawley, Recombinant Proteins chemistry, Reverse Transcriptase Inhibitors pharmacokinetics, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Thermodynamics, Triazoles pharmacokinetics, Triazoles pharmacology, Anti-HIV Agents chemical synthesis, Imidazoles chemical synthesis, Indazoles chemical synthesis, Pyrazoles chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis, Triazoles chemical synthesis
- Abstract
Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.
- Published
- 2011
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8. Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses.
- Author
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Tucker TJ, Sisko JT, Tynebor RM, Williams TM, Felock PJ, Flynn JA, Lai MT, Liang Y, McGaughey G, Liu M, Miller M, Moyer G, Munshi V, Perlow-Poehnelt R, Prasad S, Reid JC, Sanchez R, Torrent M, Vacca JP, Wan BL, and Yan Y
- Subjects
- Administration, Oral, Animals, Bromine Compounds chemical synthesis, Bromine Compounds chemistry, Crystallography, X-Ray, Drug Evaluation, Preclinical, HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase genetics, HIV Reverse Transcriptase metabolism, HIV-1 genetics, Models, Molecular, Molecular Structure, Mutation genetics, Nucleosides chemistry, Nucleosides pharmacology, Pyrazoles chemistry, Pyridines chemistry, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, HIV-1 enzymology, Pyrazoles chemical synthesis, Pyrazoles pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
- Published
- 2008
- Full Text
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9. Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer.
- Author
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Cox CD, Coleman PJ, Breslin MJ, Whitman DB, Garbaccio RM, Fraley ME, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, Davide JP, Diehl RE, Abrams MT, South VJ, Huber HE, Torrent M, Prueksaritanont T, Li C, Slaughter DE, Mahan E, Fernandez-Metzler C, Yan Y, Kuo LC, Kohl NE, and Hartman GD
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Humans, Neoplasms drug therapy, Taxoids therapeutic use, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Kinesins antagonists & inhibitors, Neoplasms enzymology, Piperidines pharmacology, Pyrroles pharmacology, Taxoids pharmacology
- Abstract
Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
- Published
- 2008
- Full Text
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10. 9-hydroxyazafluorenes and their use in thrombin inhibitors.
- Author
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Stauffer KJ, Williams PD, Selnick HG, Nantermet PG, Newton CL, Homnick CF, Zrada MM, Lewis SD, Lucas BJ, Krueger JA, Pietrak BL, Lyle EA, Singh R, Miller-Stein C, White RB, Wong B, Wallace AA, Sitko GR, Cook JJ, Holahan MA, Stranieri-Michener M, Leonard YM, Lynch JJ Jr, McMasters DR, and Yan Y
- Subjects
- Administration, Oral, Animals, Biological Availability, Blood Proteins metabolism, Crystallography, X-Ray, Dogs, Fluorenes chemistry, Fluorenes pharmacology, Half-Life, Humans, In Vitro Techniques, Macaca mulatta, Male, Microsomes, Liver metabolism, Models, Molecular, Proline chemistry, Proline pharmacology, Protein Binding, Rats, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship, Fluorenes chemical synthesis, Proline analogs & derivatives, Proline chemical synthesis, Thrombin antagonists & inhibitors
- Abstract
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (K(i) = 0.49 nM for human thrombin, 2x APTT = 0.37 microM in human plasma) and pharmacokinetic properties (F = 39%, iv T(1/2) = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-l-prolyl-2-aminomethyl-5-chlorobenzylamide (19b), with high potency (K(i) = 0.40 nM, 2x APTT = 0.18 microM), excellent pharmacokinetic properties (F = 55%, T(1/2) = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl(3)-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 microg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
- Published
- 2005
- Full Text
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11. Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.
- Author
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Young MB, Barrow JC, Glass KL, Lundell GF, Newton CL, Pellicore JM, Rittle KE, Selnick HG, Stauffer KJ, Vacca JP, Williams PD, Bohn D, Clayton FC, Cook JJ, Krueger JA, Kuo LC, Lewis SD, Lucas BJ, McMasters DR, Miller-Stein C, Pietrak BL, Wallace AA, White RB, Wong B, Yan Y, and Nantermet PG
- Subjects
- Benzylamines chemical synthesis, Benzylamines chemistry, Binding Sites, Heterocyclic Compounds chemistry, Models, Molecular, Pyrazines chemical synthesis, Pyrazines chemistry, Pyridines chemical synthesis, Pyridines chemistry, Structure-Activity Relationship, Tetrazoles chemical synthesis, Tetrazoles chemistry, Thiadiazoles chemical synthesis, Thiadiazoles chemistry, Thrombin chemistry, Triazoles chemical synthesis, Triazoles chemistry, Heterocyclic Compounds chemical synthesis, Thrombin antagonists & inhibitors
- Abstract
In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
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- 2004
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12. Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines.
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Burgey CS, Robinson KA, Lyle TA, Sanderson PE, Lewis SD, Lucas BJ, Krueger JA, Singh R, Miller-Stein C, White RB, Wong B, Lyle EA, Williams PD, Coburn CA, Dorsey BD, Barrow JC, Stranieri MT, Holahan MA, Sitko GR, Cook JJ, McMasters DR, McDonough CM, Sanders WM, Wallace AA, Clayton FC, Bohn D, Leonard YM, Detwiler TJ Jr, Lynch JJ Jr, Yan Y, Chen Z, Kuo L, Gardell SJ, Shafer JA, and Vacca JP
- Subjects
- Acetamides chemical synthesis, Acetamides pharmacology, Administration, Oral, Animals, Anticoagulants chemical synthesis, Anticoagulants pharmacology, Biological Availability, Crystallography, X-Ray, Dogs, Macaca mulatta, Models, Molecular, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Pyrazines chemical synthesis, Pyrazines pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Rats, Structure-Activity Relationship, Acetamides pharmacokinetics, Anticoagulants pharmacokinetics, Protease Inhibitors chemical synthesis, Pyrazines pharmacokinetics, Pyridines pharmacokinetics, Thrombin antagonists & inhibitors
- Abstract
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
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- 2003
- Full Text
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