Novel Trifluoromethyl Ketones as Potent Gastric Lipase Inhibitors

Abstract

Novel inhibitors of human digestive lipases, lipophilic trifluoromethyl ketones, were developed. These analogues of the natural triacylglycerol substrates of lipases were designed to contain the carbonyl group of the trifluoromethyl ketone functionality in place of the carbonyl group of the scissile ester bond at the sn-1 position. The ester bond at the sn-3 position was replaced by an ether bond, while the secondary hydroxy group was either esterified or etherified. The inhibitors were prepared starting from solketal. The inhibition of human pancreatic and gastric lipases by the trifluoromethyl ketones was studied by the monolayer technique. 5,5,5-Trifluoro-1-(dodecyloxymethyl)-4-oxopentyl decanoate is the best synthetic inhibitor of human gastric lipase ever reported (inhibition constant α₅₀=0.003).