Bioorganic & Medicinal Chemistry 2007-10-15

Mono- and disalicylic acid derivatives: PTP1B inhibitors as potential anti-obesity drugs.

Suja Shrestha, Bharat Raj Bhattarai, Keun-Hyeung Lee, Hyeongjin Cho

Index: Bioorg. Med. Chem. 15 , 6535-48, (2007)

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Abstract

A series of compounds containing one or two salicylic acid moieties were synthesized, and their efficacy to inhibit the phosphohydrolase activity of PTP1B examined. Some of the methylenedisalicylic acid derivatives were potent inhibitors of PTP1B. Of those derivatives, 3c exhibited about a 14-fold selectivity against TC-PTP, and this compound was tested in a mouse model for its efficacy to prevent diet-induced obesity. It effectively suppressed the increases in body weight and adipose mass, without any noticeable toxic effect. The compound also prevented increases in the plasma triglyceride, cholesterol, and nonesterified fatty acid concentrations; thus, expanding its therapeutic potential to other related metabolic diseases, such as hyperlipidemia and hypercholesterolemia.