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 Potent Inhibitor of Janus Kinase 2/Fms-LikeTyrosine Kinase-3 (JAK2/FLT3) for the Treatment of Rheumatoid Arthritis
Journal of Medicinal Chemistry2012Vol. 55(6), pp. 2623–2640
Citations Over TimeTop 10% of 2012 papers
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 Dymock
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 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.
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