Discovery of [(3-bromo-7-cyano-2-naphthyl)(difluoro)methyl]phosphonic acid, a potent and orally active small molecule PTP1B inhibitor.
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.
Han
Yongxin
Y
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
Belley
Michel
M
Bayly
Christopher I
CI
Colucci
John
J
Dufresne
Claude
C
Giroux
Andre
A
Lau
Cheuk K
CK
Leblanc
Yves
Y
McKay
Daniel
D
Therien
Michel
M
Wilson
Marie-Claire
MC
Skorey
Kathryn
K
Chan
Chi-Chung
CC
Scapin
Giovana
G
Kennedy
Brian P
BP
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
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