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 alpha(50)=0.003).

Differential Inhibition of Group IVA and Group VIA Phospholipases A2by 2-Oxoamides

“…We have developed a strategy for the design of inhibitors of serine-containing lipolytic enzymes, which is based on the principle that the inhibitor should consist of two components: (a) an electrophilic group that is able to react with the active-site serine residue and (b) a lipophilic segment that contains chemical motifs necessary for both specific interactions and a proper orientation in the substrate binding cleft of the enzyme . This strategy has been successfully applied in the development of lipophilic 2-oxoamides, , 2-oxoamide-, and bis-2-oxoamide- triacylglycerol analogues , as well as lipophilic aldehydes and trifluoromethyl ketones as effective inhibitors of pancreatic and gastric lipases. Accordingly, we have recently developed a novel class of 2-oxoamides that inhibit GIVA cPLA 2 . , The noted homology of GVIA iPLA 2 to GVIB PLA 2 , patatin, and GIVA cPLA 2 (lipases known to possess a catalytic Ser-Asp dyad) and the confirmation of its catalytic serine strongly suggest that GVIA iPLA 2 would be susceptible to inhibition by 2-oxoamides .…”

Triacylglycerols Based on 2-(N-tert-Butoxycarbonylamino)oleic Acid Are Potent Inhibitors of Pancreatic Lipase

“…In the past few years a number of electrophilic inhibitors of digestive lipases have been reported. The activity of various triacylglycerol analogues containing activated carbonyl groups, such as 2-oxoamide, − aldehyde, trifluoromethyl ketone against HPL and HGL has been studied by the monolayer technique.…”

Sterically Hindered Triacylglycerol Analogues as Potent Inhibitors of Human Digestive Lipases

“…[3] Recently a strategy for the rational design of lipase inhibitors was developed, which is based on the incorporation of an activated carbonyl group in a triacylglycerol structure. Thus, lipophilic 2-oxo amides, [4] aldehydes, [5] and trifluoromethylketones, [6] as well as 2-oxo amide and bis(2-oxo)amide triacylglycerol analogues [7] have been studied by the monolayer technique, and have been shown to inhibit HPL and HGL. In this work, we propose a novel approach for the development of lipolytic enzyme inhibitors.…”