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.

Keywords:

Integrins; antagonist; pulmonary; fibrosis; 伪v尾6; 伪v尾3; 尾-amino acids