title: Benzothiazole benzimidazole (S)-isothiazolidinone derivatives as protein tyrosine phosphatase-1B inhibitors.
abstract: Benzothiazole benzimidazole (S)-isothiazolidinone ((S)-IZD) derivatives 5 were discovered through a peptidomimetic modification of the tripeptide (S)-IZD protein tyrosine phosphatase 1B (PTP1B) inhibitor 1. These derivatives are potent, competitive, and reversible inhibitors of PTP1B with improved caco-2 permeability. An X-ray co-crystal structure of inhibitor 5/PTP1B at 2.2A resolution demonstrated that the benzothiazole benzimidazole forms bi-dentate H-bonds to Asp48, and the benzothiazole interacts with the surface of the protein in a solvent exposed region towards the C-site. The design, synthesis, and SAR of this novel series of benzothiazole benzimidazole containing (S)-IZD inhibitors of PTP1B are presented herein.
authors.affiliation: Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. rsparks@incyte.com
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sparks
authors.forename: Padmaja
authors.initials: P
authors.lastname: Polam
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Crawley
authors.forename: Amy
authors.initials: A
authors.lastname: Takvorian
authors.forename: Erin
authors.initials: E
authors.lastname: McLaughlin
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Nancy
authors.initials: N
authors.lastname: Taylor
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Burn
authors.forename: Phillip C C
authors.initials: PC
authors.lastname: Liu
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D013844:Thiazoles; C512915:isothiazolidinone; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases