Benzothiazole benzimidazole (S)-isothiazolidinone derivatives as protein tyrosine phosphatase-1B inhibitors.
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.
Sparks
Richard B
RB
Incyte Corporation, Discovery Chemistry, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. rsparks@incyte.com
Polam
Padmaja
P
Zhu
Wenyu
W
Crawley
Matthew L
ML
Takvorian
Amy
A
McLaughlin
Erin
E
Wei
Min
M
Ala
Paul J
PJ
Gonneville
Lucie
L
Taylor
Nancy
N
Li
Yanlong
Y
Wynn
Richard
R
Burn
Timothy C
TC
Liu
Phillip C C
PC
Combs
Andrew P
AP
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*
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