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

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.

SUBMITTER: Hart AC

PROVIDER: S-EPMC4538451 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Hart Amy C AC Schroeder Gretchen M GM Wan Honghe H Grebinski James J Inghrim Jennifer J Kempson James J Guo Junqing J Pitts William J WJ Tokarski John S JS Sack John S JS Khan Javed A JA Lippy Jonathan J Lorenzi Matthew V MV You Dan D McDevitt Theresa T Vuppugalla Ragini R Zhang Yueping Y Lombardo Louis J LJ Trainor George L GL Purandare Ashok V AV

ACS medicinal chemistry letters 20150710 8

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. ...[more]

PMID: 26288682

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