Bis-2-oxo amide triacylglycerol analogues: A novel class of potent human gastric lipase inhibitors

A novel class of potent human gastric lipase inhibitors, bis-2-oxo amide tr iacylglycerol analogues, was developed. These analogues of the natural subs trate of lipases were prepared starting from 1,3-diaminopropan-2-ol. They w ere designed to contain the 2-oxo amide functionality in place of the sciss ile ester bond at the sn-1 and sn-3 position, while the ester bond at the s n-2 position was either maintained or replaced by an ether bond. The deriva tives synthesized were tested for their ability to form stable monomolecula r films at the air/water intel face by recording their surface pressure/mol ecular area compression isotherms. The inhibition of human pancreatic and g astric lipases by the bis-2-oxo amides was studied using the monolayer tech nique with mixed films of 1,2-dicaprin containing variable proportions of e ach inhibitor. The nature of the functional group (ester or ether), as well as the chain length, at the sn-2 position influenced the potency of the in hibition. Among the compounds tested, 2-[(2-oxohexadecanoyl)amino]-1-[[(2-o xohexadecanoyl)amino]methyl]ethyl decanoate was the most potent inhibitor, causing a 50% decrease in HPL and HGL activities at 0.076 and 0.020 surface molar fractions, respectively.