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.
MeSH terms
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Benzimidazoles / chemical synthesis*
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology
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Cell Line
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Crystallography, X-Ray
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Humans
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Models, Molecular
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Molecular Mimicry
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Molecular Structure
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Oligopeptides / chemistry*
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Phosphorylation
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Phosphotyrosine / chemistry*
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases / antagonists & inhibitors*
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Protein Tyrosine Phosphatases / chemistry
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, Insulin / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
Substances
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Benzimidazoles
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Oligopeptides
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Sulfonamides
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Thiazoles
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Phosphotyrosine
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Receptor, Insulin
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Proto-Oncogene Proteins c-akt
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatases