| Literature DB >> 25453808 |
James J-W Duan1, Zhonghui Lu2, Bin Jiang2, Bingwei V Yang2, Lidia M Doweyko2, David S Nirschl2, Lauren E Haque2, Shuqun Lin2, Gregory Brown2, John Hynes2, John S Tokarski2, John S Sack2, Javed Khan2, Jonathan S Lippy2, Rosemary F Zhang2, Sidney Pitt2, Guoxiang Shen2, William J Pitts2, Percy H Carter2, Joel C Barrish2, Steven G Nadler2, Luisa M Salter-Cid2, Murray McKinnon2, Aberra Fura2, Gary L Schieven2, Stephen T Wrobleski3.
Abstract
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.Entities:
Keywords: JAK inhibitor; JAK3; Janus kinase; Pyrrolo[1,2-b]pyridazine; TYK2
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Year: 2014 PMID： 25453808 DOI： 10.1016/j.bmcl.2014.10.061
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823