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ACS Med Chem Lett. 2015 Jul 10;6(8):845-9. doi: 10.1021/acsmedchemlett.5b00225. eCollection 2015 Aug 13.

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.

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1
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.

Abstract

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

KEYWORDS:

Janus kinase 2 (JAK2); Kinase; myeloproliferative neoplasms; structure-based drug design (SBDD); thiazole

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