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

被引：87

作者：

Krenitsky, Veronique Plantevin ^{[1
]}

Nadolny, Lisa ^{[1
]}

Delgado, Mercedes ^{[1
]}

Ayala, Leticia ^{[1
]}

Clareen, Steven S. ^{[1
]}

Hilgraf, Robert ^{[1
]}

Albers, Ronald ^{[1
]}

Hegde, Sayee ^{[1
]}

D'Sidocky, Neil ^{[1
]}

Sapienza, John ^{[1
]}

Wright, Jonathan ^{[1
]}

McCarrick, Meg ^{[1
]}

Bahmanyar, Sogole ^{[1
]}

Chamberlain, Philip ^{[1
]}

Delker, Silvia L. ^{[1
]}

Muir, Jeff ^{[1
]}

Giegel, David ^{[1
]}

Xu, Li ^{[1
]}

Celeridad, Maria ^{[1
]}

Lachowitzer, Jeff ^{[1
]}

Bennett, Brydon ^{[1
]}

Moghaddam, Mehran ^{[1
]}

Khatsenko, Oleg ^{[1
]}

Katz, Jason ^{[1
]}

Fan, Rachel ^{[1
]}

Bai, April ^{[1
]}

Tang, Yang ^{[1
]}

Shirley, Michael A. ^{[1
]}

Benish, Brent ^{[1
]}

Bodine, Tracey ^{[1
]}

Blease, Kate ^{[1
]}

Raymon, Heather ^{[1
]}

Cathers, Brian E. ^{[1
]}

Satoh, Yoshitaka ^{[1
]}

机构：

[1] Celgene Corp, San Diego, CA 92121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 03期

关键词：

Idiopathic pulmonary fibrosis; Jun N-terminal kinase; Aminopurine-based JNK inhibitors; CC-930; Structure-based drug design; C-JUN; FIBROSIS; METABOLISM;

D O I：

10.1016/j.bmcl.2011.12.027

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：1433 / 1438

页数：6

共 20 条

[1] SAR and species/stereo - Selective metabolism of the sorbitol dehydrogenase inhibitor, CP-470,711 [J].