title: Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.
abstract: Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.
authors.affiliation: Incyte Corporation, Discovery Chemistry, Applied Technology, and Drug Metabolism, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA. acombs@incyte.com
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhu
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Crawley
authors.forename: Brian
authors.initials: B
authors.lastname: Glass
authors.forename: Padmaja
authors.initials: P
authors.lastname: Polam
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sparks
authors.forename: Dilip
authors.initials: D
authors.lastname: Modi
authors.forename: Amy
authors.initials: A
authors.lastname: Takvorian
authors.forename: Erin
authors.initials: E
authors.lastname: McLaughlin
authors.forename: Eddy W
authors.initials: EW
authors.lastname: Yue
authors.forename: Zelda
authors.initials: Z
authors.lastname: Wasserman
authors.forename: Michael
authors.initials: M
authors.lastname: Bower
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Mark
authors.initials: M
authors.lastname: Rupar
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Ala
authors.forename: Brian M
authors.initials: BM
authors.lastname: Reid
authors.forename: Dawn
authors.initials: D
authors.lastname: Ellis
authors.forename: Lucie
authors.initials: L
authors.lastname: Gonneville
authors.forename: Thomas
authors.initials: T
authors.lastname: Emm
authors.forename: Nancy
authors.initials: N
authors.lastname: Taylor
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
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: Gregory
authors.initials: G
authors.lastname: Hollis
authors.forename: Phillip C C
authors.initials: PC
authors.lastname: Liu
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D009842:Oligopeptides; D013449:Sulfonamides; D013844:Thiazoles; D019000:Phosphotyrosine; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases