title: Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.
abstract: The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.
authors.affiliation: Department of Drug Discovery, Exelixis, 169 Harbor Way, South San Francisco, California 94083, United States.
authors.forename: James W
authors.initials: JW
authors.lastname: Leahy
authors.forename: Chris A
authors.initials: CA
authors.lastname: Buhr
authors.forename: Henry W B
authors.initials: HW
authors.lastname: Johnson
authors.forename: Byung Gyu
authors.initials: BG
authors.lastname: Kim
authors.forename: Taegon
authors.initials: T
authors.lastname: Baik
authors.forename: Jonah
authors.initials: J
authors.lastname: Cannoy
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Forsyth
authors.forename: Joon Won
authors.initials: JW
authors.lastname: Jeong
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lee
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Ma
authors.forename: Kevin
authors.initials: K
authors.lastname: Noson
authors.forename: Longcheng
authors.initials: L
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Eric
authors.initials: E
authors.lastname: Brooks
authors.forename: Paul
authors.initials: P
authors.lastname: Foster
authors.forename: Leanne
authors.initials: L
authors.lastname: Goon
authors.forename: Nathan
authors.initials: N
authors.lastname: Heald
authors.forename: Charles
authors.initials: C
authors.lastname: Holst
authors.forename: Christopher
authors.initials: C
authors.lastname: Jaeger
authors.forename: Scott
authors.initials: S
authors.lastname: Lam
authors.forename: Julie
authors.initials: J
authors.lastname: Lougheed
authors.forename: Lam
authors.initials: L
authors.lastname: Nguyen
authors.forename: Arthur
authors.initials: A
authors.lastname: Plonowski
authors.forename: Joanne
authors.initials: J
authors.lastname: Song
authors.forename: Thomas
authors.initials: T
authors.lastname: Stout
authors.forename: Xiang
authors.initials: X
authors.lastname: Wu
authors.forename: Michael F
authors.initials: MF
authors.lastname: Yakes
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Peter
authors.initials: P
authors.lastname: Lamb
authors.forename: Olivia
authors.initials: O
authors.lastname: Raeber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008163:Luminescent Measurements; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D013449:Sulfonamides; D013450:Sulfones; D051057:Proto-Oncogene Proteins c-akt