title: Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B.
abstract: Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.
authors.affiliation: Department of Medicinal Chemistry Research 1, 4, and 5 and Drug Metabolism, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. HSA@novonordisk.com
authors.forename: Henrik Sune
authors.initials: HS
authors.lastname: Andersen
authors.forename: Ole H
authors.initials: OH
authors.lastname: Olsen
authors.forename: Lars F
authors.initials: LF
authors.lastname: Iversen
authors.forename: Anette L P
authors.initials: AL
authors.lastname: Sørensen
authors.forename: Steen B
authors.initials: SB
authors.lastname: Mortensen
authors.forename: Michael S
authors.initials: MS
authors.lastname: Christensen
authors.forename: Sven
authors.initials: S
authors.lastname: Branner
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Hansen
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Lau
authors.forename: Lone
authors.initials: L
authors.lastname: Jeppesen
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Moran
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.forename: Farid
authors.initials: F
authors.lastname: Bakir
authors.forename: Luke
authors.initials: L
authors.lastname: Judge
authors.forename: Manou
authors.initials: M
authors.lastname: Shahbaz
authors.forename: Tassie
authors.initials: T
authors.lastname: Collins
authors.forename: Todd
authors.initials: T
authors.lastname: Vo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Newman
authors.forename: William C
authors.initials: WC
authors.lastname: Ripka
authors.forename: Niels Peter H
authors.initials: NP
authors.lastname: Møller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D003847:Deoxyglucose / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; D013876:Thiophenes; D003847:Deoxyglucose; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; C516610:Ptpn1 protein, rat