title: Discovery of Orally Efficacious Phosphoinositide 3-Kinase δ Inhibitors with Improved Metabolic Stability.
abstract: 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.
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Chandrasekhar
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Evarts
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Kristen
authors.initials: K
authors.lastname: Forseth
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Haran
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ip
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Kashishian
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Musong
authors.initials: M
authors.lastname: Kim
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: David
authors.initials: D
authors.lastname: Koditek
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Sandy
authors.initials: S
authors.lastname: Koppenol
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Latesh
authors.initials: L
authors.lastname: Lad
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Eve-Irene
authors.initials: EI
authors.lastname: Lepist
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Mary E
authors.initials: ME
authors.lastname: McGrath
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Stephane
authors.initials: S
authors.lastname: Perreault
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Armando G
authors.initials: AG
authors.lastname: Villaseñor
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Bart H
authors.initials: BH
authors.lastname: Steiner
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Therrien
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Treiberg
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips