ABSTRACT
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.
Subject(s)
2-Aminopurine/chemistry , 2-Aminopurine/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Purines/chemistry , Reperfusion Injury/enzymology , Animals , Catalytic Domain , Dogs , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haplorhini , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Purines/pharmacology , Rats , Reperfusion Injury/drug therapy , Structure-Activity RelationshipABSTRACT
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
