title: Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.
abstract: The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. peipei.kung@pfizer.com
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Kung
authors.forename: Buwen
authors.initials: B
authors.lastname: Huang
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.forename: Joe Zhongxiang
authors.initials: JZ
authors.lastname: Zhou
authors.forename: Jeff
authors.initials: J
authors.lastname: Wang
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Digits
authors.forename: Judith
authors.initials: J
authors.lastname: Skaptason
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: David
authors.initials: D
authors.lastname: Neul
authors.forename: Michael
authors.initials: M
authors.lastname: Zientek
authors.forename: Jeff
authors.initials: J
authors.lastname: Elleraas
authors.forename: Pramod
authors.initials: P
authors.lastname: Mehta
authors.forename: Min-Jean
authors.initials: MJ
authors.lastname: Yin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.forename: Ketan S
authors.initials: KS
authors.lastname: Gajiwala
authors.forename: Caroline
authors.initials: C
authors.lastname: Rodgers
authors.forename: Jay F
authors.initials: JF
authors.lastname: Davies
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gehring
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles