title: Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.
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.
authors.affiliation: Celgene Corporation, 4550 Towne Centre Court, San Diego, CA 92121, USA. vplantev@celgene.com
authors.forename: Véronique
authors.initials: V
authors.lastname: Plantevin Krenitsky
authors.forename: Lisa
authors.initials: L
authors.lastname: Nadolny
authors.forename: Mercedes
authors.initials: M
authors.lastname: Delgado
authors.forename: Leticia
authors.initials: L
authors.lastname: Ayala
authors.forename: Steven S
authors.initials: SS
authors.lastname: Clareen
authors.forename: Robert
authors.initials: R
authors.lastname: Hilgraf
authors.forename: Ronald
authors.initials: R
authors.lastname: Albers
authors.forename: Sayee
authors.initials: S
authors.lastname: Hegde
authors.forename: Neil
authors.initials: N
authors.lastname: D'Sidocky
authors.forename: John
authors.initials: J
authors.lastname: Sapienza
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wright
authors.forename: Meg
authors.initials: M
authors.lastname: McCarrick
authors.forename: Sogole
authors.initials: S
authors.lastname: Bahmanyar
authors.forename: Philip
authors.initials: P
authors.lastname: Chamberlain
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Delker
authors.forename: Jeff
authors.initials: J
authors.lastname: Muir
authors.forename: David
authors.initials: D
authors.lastname: Giegel
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Maria
authors.initials: M
authors.lastname: Celeridad
authors.forename: Jeff
authors.initials: J
authors.lastname: Lachowitzer
authors.forename: Brydon
authors.initials: B
authors.lastname: Bennett
authors.forename: Mehran
authors.initials: M
authors.lastname: Moghaddam
authors.forename: Oleg
authors.initials: O
authors.lastname: Khatsenko
authors.forename: Jason
authors.initials: J
authors.lastname: Katz
authors.forename: Rachel
authors.initials: R
authors.lastname: Fan
authors.forename: April
authors.initials: A
authors.lastname: Bai
authors.forename: Yang
authors.initials: Y
authors.lastname: Tang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Shirley
authors.forename: Brent
authors.initials: B
authors.lastname: Benish
authors.forename: Tracey
authors.initials: T
authors.lastname: Bodine
authors.forename: Kate
authors.initials: K
authors.lastname: Blease
authors.forename: Heather
authors.initials: H
authors.lastname: Raymon
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cathers
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Satoh
mesh_terms: D000284:Administration, Oral; D000818:Animals; D020134:Catalytic Domain; D003511:Cyclohexanols / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D000882:Haplorhini; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C570789:4-(9-(tetrahydrofuran-3-yl))-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylaminocyclohexan-1-ol; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D011687:Purines; D048670:MAP Kinase Kinase 4