Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration.
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.
Liu
Ding-Guo
DG
Laboratory of Medicinal Chemistry, CCR, NCI, NIH, NCI-Frederick, Frederick, MD 21702, USA.
Gao
Yang
Y
Voigt
Johannes H
JH
Lee
Kyeong
K
Nicklaus
Marc C
MC
Wu
Li
L
Zhang
Zhong-Yin
ZY
Burke
Terrence R
TR
D024342:Amino Acids, Acidic / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides; D014867:Water / Q000737:chemistry
D024342:Amino Acids, Acidic; D004791:Enzyme Inhibitors; D004798:Enzymes; D013449:Sulfonamides; D014867:Water; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases