Structure Activity Relationships of 伪v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents
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- 作者：James Adams ; Edward C. Anderson ; Emma E. Blackham ; Yin Wa Ryan Chiu ; Thomas Clarke ; Natasha Eccles ; Luke A. Gill ; Joshua J. Haye ; Harvey T. Haywood ; Christian R. Hoenig ; Marius Kausas ; Joelle Le ; Hannah L. Russell ; Christopher Smedley ; William J. Tipping ; Tom Tongue ; Charlotte C. Wood ; Jason Yeung ; James E. Rowedder ; M. Jonathan Fray ; Thomas McInally ; Simon J. F. Macdonald
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：November 13, 2014
- 年：2014
- 卷：5
- 期：11
- 页码：1207-1212
- 全文大小：272K
- ISSN：1948-5875
文摘
Antagonism of 伪v尾6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an 伪v尾3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved 伪v尾6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan 伪v antagonists having ca. 100 nM potency against 伪v尾3, 伪v尾5, 伪v尾6, and 伪v尾8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for 伪v尾3 and 伪v尾5.