title: The development of potent non-peptidic PTP-1B inhibitors.
abstract: The SAR from our peptide libraries was exploited to design a series of potent deoxybenzoin PTP-1B inhibitors. The introduction of an ortho bromo substituent next to the difluoromethylphosphonate warhead gave up to 20-fold increase in potency compared to the desbromo analogues. In addition, these compounds were orally bioavailable and active in the animal models of non-insulin dependent diabetes mellitus (NIDDM).
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire, Dorval, Canada H9R 4P8. claude_l_dufresne@merck.com
authors.forename: Claude
authors.initials: C
authors.lastname: Dufresne
authors.forename: Patrick
authors.initials: P
authors.lastname: Roy
authors.forename: Zhaoyin
authors.initials: Z
authors.lastname: Wang
authors.forename: Ernest
authors.initials: E
authors.lastname: Asante-Appiah
authors.forename: Wanda
authors.initials: W
authors.lastname: Cromlish
authors.forename: Yves
authors.initials: Y
authors.lastname: Boie
authors.forename: Farnaz
authors.initials: F
authors.lastname: Forghani
authors.forename: Sylvie
authors.initials: S
authors.lastname: Desmarais
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wang
authors.forename: Kathryn
authors.initials: K
authors.lastname: Skorey
authors.forename: Deena
authors.initials: D
authors.lastname: Waddleton
authors.forename: Chidambaram
authors.initials: C
authors.lastname: Ramachandran
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kennedy
authors.forename: Lijing
authors.initials: L
authors.lastname: Xu
authors.forename: Robert
authors.initials: R
authors.lastname: Gordon
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Yves
authors.initials: Y
authors.lastname: Leblanc
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001573:Benzoin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007313:Insecta; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D001573:Benzoin