Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor

Bioorg Med Chem Lett. 2012 Feb 1;22(3):1433-8. doi: 10.1016/j.bmcl.2011.12.027. Epub 2011 Dec 10.

Abstract

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.

MeSH terms

  • Administration, Oral
  • Animals
  • Catalytic Domain
  • Cyclohexanols / administration & dosage
  • Cyclohexanols / chemistry*
  • Cyclohexanols / pharmacology*
  • Dogs
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Haplorhini
  • Idiopathic Pulmonary Fibrosis / drug therapy
  • Inhibitory Concentration 50
  • MAP Kinase Kinase 4 / antagonists & inhibitors*
  • Models, Molecular
  • Molecular Structure
  • Purines / administration & dosage
  • Purines / chemistry*
  • Purines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • 4-(9-(tetrahydrofuran-3-yl))-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylaminocyclohexan-1-ol
  • Cyclohexanols
  • Enzyme Inhibitors
  • Purines
  • MAP Kinase Kinase 4