ABSTRACT
Identification of singleton P2X7 inhibitor 1 from HTS gave a pharmacophore that eventually turned into potential clinical candidates 17 and 19. During development, a number of issues were successfully addressed, such as metabolic stability, plasma stability, GSH adduct formation, and aniline mutagenicity. Thus, careful modification of the molecule, such as conversion of the 1,4-dihydropyridinone to the 1,2-dihydropyridinone system, proper substitution at C-5â³, and in some cases addition of fluorine atoms to the aniline ring allowed for the identification of a novel class of potent P2X7 inhibitors suitable for evaluating the role of P2X7 in inflammatory, immune, neurologic, or musculoskeletal disorders.
Subject(s)
Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Receptors, Purinergic P2X7/metabolism , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Halogenation , HumansABSTRACT
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
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.