ABSTRACT
A novel, potent and selective quinazolinone series of inhibitors of p38α MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG 'out' to DFG 'in' as the inhibitor size was reduced to improve overall properties.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Piperazines/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Proteins/chemistry , Crystallography, X-Ray , Dogs , Drug Discovery , Humans , Inflammation/drug therapy , Mitogen-Activated Protein Kinase 14/metabolism , Models, Molecular , Molecular Weight , Piperazines/chemistry , Piperazines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Directed screening has identified a novel series of non-zinc binding MMP13 inhibitors that possess good levels of activity whilst demonstrating excellent selectivity over related MMPs. A lead optimisation campaign has delivered compounds with enhanced MMP13 potency, good selectivity and acceptable bioavailability profiles leading to a predicted twice-a-day dosing regimen in man.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Matrix Metalloproteinase 13/chemistry , Matrix Metalloproteinase Inhibitors , Zinc/chemistry , Animals , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Osteoarthritis/drug therapy , Rats , Solubility , Structure-Activity RelationshipABSTRACT
Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Zinc/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Matrix Metalloproteinase 13/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
An imidazole series of cyclin-dependent kinase (CDK) inhibitors has been developed. Protein inhibitor structure determination has provided an understanding of the emerging structure activity trends for the imidazole series. The introduction of a methyl sulfone at the aniline terminus led to a more orally bioavailable CDK inhibitor that was progressed into clinical development.
