ABSTRACT
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 indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Crystallography, X-Ray , Indazoles/chemistry , Indazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/chemistry , Phosphorylation , Structure-Activity RelationshipABSTRACT
We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.
Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrroles/chemical synthesis , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/enzymology , Blood Proteins/metabolism , Crystallography, X-Ray , Humans , Mice , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Protein Binding , Pyrazines/pharmacology , Pyrazines/toxicity , Pyrroles/pharmacology , Pyrroles/toxicity , Structure-Activity Relationship , Syk KinaseABSTRACT
A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.
Subject(s)
JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Crystallography, X-Ray , Drug Design , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Rats , Structure-Activity Relationship , Triazoles/chemical synthesisABSTRACT
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
The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
Subject(s)
Drug Discovery/methods , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridones/pharmacology , Pyridones/pharmacokinetics , Pyrimidines/pharmacology , Pyrimidines/pharmacokinetics , Administration, Oral , Arthritis, Rheumatoid/drug therapy , Biological Availability , Cell Line , Clinical Trials as Topic , Humans , Mitogen-Activated Protein Kinase 14/chemistry , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyridones/administration & dosage , Pyridones/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.
