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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.

ABSTRACT: JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

SUBMITTER: Wan H 

PROVIDER: S-EPMC4538448 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.

Wan Honghe H   Schroeder Gretchen M GM   Hart Amy C AC   Inghrim Jennifer J   Grebinski James J   Tokarski John S JS   Lorenzi Matthew V MV   You Dan D   Mcdevitt Theresa T   Penhallow Becky B   Vuppugalla Ragini R   Zhang Yueping Y   Gu Xiaomei X   Iyer Ramaswamy R   Lombardo Louis J LJ   Trainor George L GL   Ruepp Stefan S   Lippy Jonathan J   Blat Yuval Y   Sack John S JS   Khan Javed A JA   Stefanski Kevin K   Sleczka Bogdan B   Mathur Arvind A   Sun Jung-Hui JH   Wong Michael K MK   Wu Dauh-Rurng DR   Li Peng P   Gupta Anuradha A   Arunachalam P N PN   Pragalathan Bala B   Narayanan Sankara S   K C Nanjundaswamy N   Kuppusamy Prakasam P   Purandare Ashok V AV  

ACS medicinal chemistry letters 20150712 8

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile. ...[more]

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