2. Academic Validation
  3. 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-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis

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-like tyrosine kinase-3 (JAK2/FLT3) for the treatment of rheumatoid arthritis

  • J Med Chem. 2012 Mar 22;55(6):2623-40. doi: 10.1021/jm201454n.
Anthony D William 1,  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
Affiliations

Affiliation

  • 1 S BIO Pte. Ltd., 1 Science Park Road, #05-09 The Capricorn, Singapore Science Park II, Singapore 117528. [email protected]
PMID: 22339472 DOI: 10.1021/jm201454n
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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