Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Metabolic Stability.

Autor: Patel L; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Chandrasekhar J; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Evarts J; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Forseth K; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Haran AC; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Ip C; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Kashishian A; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Kim M; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Koditek D; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Koppenol S; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Lad L; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Lepist EI; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., McGrath ME; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Perreault S; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Puri KD; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Villaseñor AG; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Somoza JR; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Steiner BH; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Therrien J; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Treiberg J; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States., Phillips G; Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2016 Oct 13; Vol. 59 (19), pp. 9228-9242. Date of Electronic Publication: 2016 Oct 03.
DOI: 10.1021/acs.jmedchem.6b01169
Abstrakt: Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
Databáze: MEDLINE
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