title: Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.
abstract: An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
authors.affiliation: Medicinal Chemistry, Pfizer, Pearl River, NY 10965, United States. 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: Zhong
authors.initials: Z
authors.lastname: Li
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: Antonia
authors.initials: A
authors.lastname: Nikitenko
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: Erik
authors.initials: E
authors.lastname: Vogan
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Mark
authors.initials: M
authors.lastname: Johnson
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D015415:Biomarkers / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D047028:Macrocyclic Compounds / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015415:Biomarkers; D018841:HSP90 Heat-Shock Proteins; D047028:Macrocyclic Compounds; C037689:benzamide