Discovery of the Macrocycle (9 E)-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) …

…, D Chen, CP Lee, ET Sun, R Jayaraman…

Index: William, Anthony D.; Lee, Angeline C.-H.; Poulsen, Anders; Goh, Kee Chuan; Madan, Babita; Hart, Stefan; Tan, Evelyn; Wang, Haishan; Nagaraj, Harish; Chen, Dizhong; Lee, Chai Ping; Sun, Eric T.; Jayaraman, Ramesh; Pasha, Mohammad Khalid; Ethirajulu, Kantharaj; Wood, Jeanette M.; Dymock, Brian W. Journal of Medicinal Chemistry, 2012 , vol. 55, # 6 p. 2623 - 2640

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Citation Number: 20

Abstract

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 ...