Subject(s)
Community Pharmacy Services , Pharmacists , Chronic Disease , Humans , Medication Adherence , Primary Health Care , Professional RoleABSTRACT
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Quinolines/pharmacology , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Humans , Models, Molecular , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacokineticsABSTRACT
A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.
Subject(s)
4-Quinolones/pharmacology , Drug Discovery , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , 4-Quinolones/chemical synthesis , 4-Quinolones/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Learnings from previous Roche p38-selective inhibitors were applied to a new fragment hit, which was optimized to a potent, exquisitely selective preclinical lead with a good pharmacokinetic profile.
Subject(s)
Drug Design , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Animals , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , RatsABSTRACT
Optimization of the amino acid side chain and the N-alkyl group of the sulfonamide of amino acid derived sulfonamide hydroxamates is discussed. The solid-phase synthesis of these potent inhibitors of procollagen C-proteinase (PCP) is presented. In addition, novel carboxylic acid sulfonamides were discovered to be PCP inhibitors.