Lead identification of novel and selective TYK2 inhibitors

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• 作者：Jun Liang ; Vickie Tsui ; Anne Van Abbema ; Liang Bao ; Kathy Barrett ; Maureen Beresini ; Leo Berezhkovskiy ; Wade S. Blair ; Christine Chang ; James Driscoll ; Charles Eigenbrot ; Nico Ghilardi ; Paul Gibbons ; Jason Halladay ; Adam Johnson ; Pawan Bir Kohli ; Yingjie Lai ; Marya Liimatta ; Priscilla Mantik ; Kapil Menghrajani ; et al.
• 关键词：Kinase inhibitor ; Janus family kinase ; Structure&ndash ; activity relationship ; Crystal structure ; Hit to lead ; Immunology
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：67
• 期：Complete
• 页码：175-187
• 全文大小：2096 K

文摘

A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.