title: Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor.
abstract: A series of quinoline/naphthalene-difluoromethylphosphonates were prepared and were found to be potent PTP1B inhibitors. Most of these compounds bearing polar functionalities or large lipophilic residues did not show appreciable oral bioavailability in rodents while small and less polar analogs displayed moderate to good oral bioavailability. The title compound was found to have the best overall potency and pharmacokinetic profile and was found to be efficacious in animal models of diabetes and cancer.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, PO Box 1005, Pointe-Claire-Dorval, Que., Canada. yongxin_han@merck.com
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
authors.forename: Michel
authors.initials: M
authors.lastname: Belley
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Bayly
authors.forename: John
authors.initials: J
authors.lastname: Colucci
authors.forename: Claude
authors.initials: C
authors.lastname: Dufresne
authors.forename: Andre
authors.initials: A
authors.lastname: Giroux
authors.forename: Cheuk K
authors.initials: CK
authors.lastname: Lau
authors.forename: Yves
authors.initials: Y
authors.lastname: Leblanc
authors.forename: Daniel
authors.initials: D
authors.lastname: McKay
authors.forename: Michel
authors.initials: M
authors.lastname: Therien
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Wilson
authors.forename: Kathryn
authors.initials: K
authors.lastname: Skorey
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Giovana
authors.initials: G
authors.lastname: Scapin
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D003920:Diabetes Mellitus / Q000139:chemically induced; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D000882:Haplorhini; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000139:chemically induced; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: C529684:((3-bromo-7-cyano-2-naphthyl)(difluoro)methyl)phosphonic acid; D006846:Hydrocarbons, Halogenated; D009281:Naphthalenes; D063065:Organophosphonates; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1