Discovery of the Macrocycle (9E)-15-(2-(Pyrrolidin-1-yl)ethoxy)-7,12,25-trioxa-19,21,24-triaza-tetracyclo[18.3.1.1(2,5).1(14,18)]hexacosa-1(24),2,4,9,14(26),15,17,20,22-nonaene (SB1578), a Pote
详细信息 查看全文
- 作者：Anthony D. William ; Angeline C.-H. Lee ; Anders Poulsen ; Kee Chuan Goh ; Babita Madan ; Stefan Hart ; Evelyn Tan ; Haishan Wang ; Harish Nagaraj ; Dizhong Chen ; Chai Ping Lee ; Eric T. Sun ; Ramesh Jayaraman ; Mohammad Khalid Pasha ; Kantharaj Ethirajulu ; Jeanette M. Wood ; Brian W. Dymock
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：March 22, 2012
- 年：2012
- 卷：55
- 期：6
- 页码：2623-2640
- 全文大小：652K
- 年卷期：v.55,no.6(March 22, 2012)
- ISSN：1520-4804
文摘
Herein, we describe the synthesis and SAR of a series of small molecule macrocycles that selectively inhibit JAK2 kinase within the JAK family and FLT3 kinase. Following a multiparameter optimization of a key aryl ring of the previously described SB1518 (pacritinib), the highly soluble 14l was selected as the optimal compound. Oral efficacy in the murine collagen-induced arthritis (CIA) model for rheumatoid arthritis (RA) supported 14l as a potential treatment for autoimmune diseases and inflammatory disorders such as psoriasis and RA. Compound 14l (SB1578) was progressed into development and is currently undergoing phase 1 clinical trials in healthy volunteers.