title: Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.
abstract: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
authors.affiliation: Medicinal Chemistry, Pfizer, 401 N Middletown Road, Pearl River, NY 10965, United States. chzapf@gmail.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: Mercy
authors.initials: M
authors.lastname: Otteng
authors.forename: Charles
authors.initials: C
authors.lastname: Ingalls
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Golas
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
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: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D005456:Fluorescent Dyes; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D062367:ortho-Aminobenzoates; C000219:anthranilamide