title: Probing acid replacements of thiophene PTP1B inhibitors.
abstract: The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Wan
authors.forename: Bruce
authors.initials: B
authors.lastname: Follows
authors.forename: Steve
authors.initials: S
authors.lastname: Kirincich
authors.forename: Douglas
authors.initials: D
authors.lastname: Wilson
authors.forename: Eva
authors.initials: E
authors.lastname: Binnun
authors.forename: Weixin
authors.initials: W
authors.lastname: Xu
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Smith
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: May
authors.initials: M
authors.lastname: Tam
authors.forename: David
authors.initials: D
authors.lastname: Erbe
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Jinbo
authors.initials: J
authors.lastname: Lee
mesh_terms: D000143:Acids / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000145:classification; D006801:Humans; D015394:Molecular Structure; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000143:Acids; D004791:Enzyme Inhibitors; D013876:Thiophenes; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases