ABSTRACT
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Isoquinolines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase , Crystallography, X-Ray , Drug Design , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolismABSTRACT
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
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.