Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.
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.
Combs
Andrew P
AP
Incyte Corporation, Discovery Chemistry, Applied Technology, and Drug Metabolism, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA. acombs@incyte.com
Zhu
Wenyu
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Crawley
Matthew L
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Glass
Brian
B
Polam
Padmaja
P
Sparks
Richard B
RB
Modi
Dilip
D
Takvorian
Amy
A
McLaughlin
Erin
E
Yue
Eddy W
EW
Wasserman
Zelda
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Bower
Michael
M
Wei
Min
M
Rupar
Mark
M
Ala
Paul J
PJ
Reid
Brian M
BM
Ellis
Dawn
D
Gonneville
Lucie
L
Emm
Thomas
T
Taylor
Nancy
N
Yeleswaram
Swamy
S
Li
Yanlong
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Wynn
Richard
R
Burn
Timothy C
TC
Hollis
Gregory
G
Liu
Phillip C C
PC
Metcalf
Brian
B
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
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