title: Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.
abstract: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
authors.affiliation: Medicinal Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, USA. christoph.zapf@pfizer.com
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Zapf
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Bloom
authors.forename: Jamie L
authors.initials: JL
authors.lastname: McBean
authors.forename: Russell G
authors.initials: RG
authors.lastname: Dushin
authors.forename: Thomas
authors.initials: T
authors.lastname: Nittoli
authors.forename: Charles
authors.initials: C
authors.lastname: Ingalls
authors.forename: Alan G
authors.initials: AG
authors.lastname: Sutherland
authors.forename: John P
authors.initials: JP
authors.lastname: Sonye
authors.forename: Clark N
authors.initials: CN
authors.lastname: Eid
authors.forename: Jennifer
authors.initials: J
authors.lastname: Golas
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Frank
authors.initials: F
authors.lastname: Boschelli
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Erik
authors.initials: E
authors.lastname: Vogan
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; C037689:benzamide