title: 2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors.
abstract: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.
authors.affiliation: Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Kaplan
authors.affiliation: Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Novikov
authors.affiliation: Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Stevens
authors.affiliation: Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|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. , 199 E Blaine Street, Seattle, Washington 98102, United States.|Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Yeung
authors.affiliation: Gilead Sciences, Inc. , 199 E Blaine Street, Seattle, Washington 98102, United States.|Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000633:toxicity; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D052999:Quinazolinones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution
chemical_list: C000611074:2,4-diamino-6-(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethylamino)pyrimidine-5-carbonitrile; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D052999:Quinazolinones; C012070:2,4,6-triaminopyrimidine; D003094:Collagen; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human