Studies on Hypolipidemic Agents. II. Synthesis of 1-Arenesulfonyloxy-2-alkanone Derivatives as Potent Esterase Inhibitors and Hypolipidemic Agents

Abstract

Many 2-oxoalkyl arenesulfonate derivatives having straight or branched alkyl chains of different lengths, 2-oxoalkyl bis-arenesulfonate derivatives, and alkyl arenesulfonate derivatives having a ketal moiety at the 2-position on the alkyl chain were synthesized, and their esterase-inhibitory activities, as well as hypolipidemic activities, were evaluated. Among these compounds, l-(2,4,6-trimethylbenzenesulfonyloxy)-2-dodecanone (III-lu), and l-(2,3,4,6-tetramethylbenzenesulfonyloxy)-2-hexanone (III-lw), -2-octanone (III-lx) and -2-dec-anone (III-ly) exhibited potent esterase-inhibitory activities (IC50 = 3 x 10–10, 2 x 10-10, 2 x 10-10 and 3 x 10-11M, respectively). However, the sulfonate (XV) having a ketal moiety on the alkyl chain and the bis-sulfonate (XVI) exhibited low inhibitory activities toward esterase in comparison with III and XII. Most of the compounds III and some of the compounds XII exhibited potent hypolipidemic activities corresponding to more than 50% lipid-lowering effect (plasma triglyceride and cholesterol ester) in vivo. The structure-activity relationships of these compounds are discussed. © 1986, The Pharmaceutical Society of Japan. All rights reserved.