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3 results on '"Mike Westby"'

1. The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile-Part 1

Author

Kathy F. K. Cheung, Jean-Yves Chiva, Satish Dayal, Darren Stead, Carly L. Nichols, Rob Webster, Lee R. Roberts, David Stonehouse, Felice Daverio, Iain Gardner, Andrew Pike, Michael Paradowski, David C. Blakemore, Gilles H. Goetz, Lesa Watson, Chris Pickford, Jared B.J. Milbank, Ye Che, Robert Wybrow, Florian Wakenhut, Keith Statham, Caroline Smith-Burchnell, Samuel Crook, Fiona M. Adam, David C. Pryde, David Leese, Mike Westby, Duncan Hay, Stephen M. Shaw, and Tram T. Tran

Subjects
Daclatasvir, Hepatitis C virus, Hepacivirus, Drug Evaluation, Preclinical, Drug resistance, Viral Nonstructural Proteins, Pharmacology, medicine.disease_cause, Antiviral Agents, Biochemistry, Virus, Cell Line, Structure-Activity Relationship, Dogs, Quinoxalines, Drug Resistance, Viral, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, Potency, Protease Inhibitors, General Pharmacology, Toxicology and Pharmaceutics, NS5A, biology, Organic Chemistry, Valine, biology.organism_classification, Virology, Rats, Microsomes, Liver, Molecular Medicine, Half-Life, medicine.drug
Abstract

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.

Published
2014
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2. Comparison of the Non-Nucleoside Reverse Transcriptase Inhibitor Lersivirine with its Pyrazole and Imidazole Isomers

Author

Lyn H. Jones, Donald Stuart Middleton, Sandra D. Newman, Romuald Corbau, Gill Allan, Charles E. Mowbray, Rob Webster, Mike Westby, and Christopher Phillips

Subjects
Pharmacology, Reverse-transcriptase inhibitor, Drug discovery, Stereochemistry, Organic Chemistry, Pyrazole, Biochemistry, Nucleoside Reverse Transcriptase Inhibitor, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Molecular Medicine, Imidazole, Lersivirine, medicine.drug
Abstract

Lersivirine is a potent non-nucleoside reverse transcriptase inhibitor with exceptional mutant resilience. Here, we compare the pharmacological and pharmacokinetic profile of lersivirine with its pyrazole and imidazole isomers and briefly explore the profile of these series. This work establishes lersivirine as the outstanding molecule in this set.

Published
2011
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3. Optimization of 5-Aryloxyimidazole Non-Nucleoside Reverse Transcriptase Inhibitors

Author

Gill Allan, Amy Randall, Sandra D. Newman, Romuald Corbau, Charles E. Mowbray, David Howard Williams, Manos Perros, Mike Westby, Duncan Hay, Donald Stuart Middleton, Hannah Vuong, Lyn H. Jones, and Rob Webster

Subjects
Chemistry, Pharmaceutical, Allosteric regulation, Human immunodeficiency virus (HIV), Biology, medicine.disease_cause, Antiviral Agents, Biochemistry, Cell Line, Nucleoside Reverse Transcriptase Inhibitor, Inhibitory Concentration 50, Drug Resistance, Viral, Drug Discovery, medicine, Humans, Potency, General Pharmacology, Toxicology and Pharmaceutics, Pharmacology, chemistry.chemical_classification, Acquired Immunodeficiency Syndrome, Mutation, Sulfur Compounds, Organic Chemistry, Imidazoles, virus diseases, Metabolic stability, HIV Reverse Transcriptase, Reverse transcriptase, Enzyme, Models, Chemical, chemistry, Drug Design, Reverse Transcriptase Inhibitors, Molecular Medicine, Allosteric Site
Abstract

A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their vulnerability to mutations in the allosteric binding site of reverse transcriptase that can result in the development of a resistant virus. Herein we present the optimization of a series of 5-aryloxy imidazoles, which possess a balanced pharmacological profile against both wild-type enzyme and the clinically relevant mutations K103N and Y181C. Subtle structural changes were used to probe structure-activity relationships relating to both potency and metabolic stability, which led to an imidazole derivative with an impressive overall profile.

Published
2008
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