Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration.

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Liu DG, Gao Y, Voigt JH, Lee K, Nicklaus MC, Wu L, Zhang ZY, Burke TR Jr

Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration.

Bioorg Med Chem Lett. 2003 Sep 15;13(18):3005-7.

PubMed ID

12941322 [ View in PubMed

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Abstract

Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
6-(DIFLUORO-PHOSPHONO-METHYL)-NAPHTHALENE-2-CARBOXYLIC ACID	Tyrosine-protein phosphatase non-receptor type 1	Ki (nM)	22000	N/A	N/A	Details