Mitigation of reactive metabolite formation for a series of 3-amino-2-pyridone inhibitors of Bruton’s tyrosine kinase (BTK)
详细信息 查看全文
- 作者：Yan Lou ; yan.lou@gmail.com ; Francisco Lopez ; Yongying Jiang ; Xiaochun Han ; Chris Brotherton ; Roland Billedeau ; Steve Gabriel ; Shelly Gleason ; David M. Goldstein ; Ramona Hilgenkamp ; Buelent Kocer ; Lucja Orzechowski ; Jenny Tan ; Peter Wovkulich ; Bo Wen ; David Fry ; Paola Di Lello ; Lucy Chen ; Fang-jie Zhang ; Jennifer Fretland ; Anjali Nangia ; Tian Yang ; Timothy D. Owens
- 关键词：Bruton&rsquo ; s tyrosine kinase ; BTK ; Reactive metabolite ; Covalent binding ; Glutathione adduct
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2017
- 出版时间：1 February 2017
- 年：2017
- 卷：27
- 期：3
- 页码：632-635
- 全文大小：844 K
- 卷排序：27
文摘
Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e.g. compound 1 has a value of 459 pmol/mg protein in the microsomal covalent binding assay. Parallel approaches were taken to successfully resolve the issues: establishment of a predictive screening assay with correlation association of covalent binding assay, identification of the origin of reactive metabolite formation using MS/MS analysis of HLM as well as isolation and characterization of GSH adducts. This ultimately led to the discovery of compound 7 (RN941) with significantly reduced covalent binding of 26 pmol/mg protein.