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Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors.

Abstract：

:A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Hynes J Jr,Wu H,Kempson J,Duan JJ,Lu Z,Jiang B,Stachura S,Tokarski JS,Sack JS,Khan JA,Lippy JS,Zhang RF,Pitt S,Shen G,Gillooly K,McIntyre K,Carter PH,Barrish JC,Nadler SG,Salter-Cid LM,Fura A,Schieven GL,Pitts

doi

10.1016/j.bmcl.2017.05.043

subject

Has Abstract

pub_date

2017-07-15 00:00:00

pages

3101-3106

issue

14

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)30524-3

journal_volume

27

pub_type

杂志文章

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