Design, synthesis and biological evaluation of monoglyceride lipase inhibitors guided by dipeptidyl peptidase IV inhibitors

Abstract

This study aimed to develop inhibitors of monoglyceride lipase, a key enzyme in lipolysis linked to insulin resistance, using structural frameworks derived from dipeptidyl peptidase IV inhibitors. Two series of compounds were synthesized—one based on an amantadine scaffold and the other on a pyrimidinyl piperazine structure—and their design was guided by molecular docking studies that predicted favorable binding within the enzyme’s active site. Biological evaluation revealed that selected compounds exhibited potent inhibitory activity, with half maximal inhibitory concentrations in the low to mid nanomolar range. In particular, compounds from the pyrimidinyl piperazine series demonstrated high selectivity for monoglyceride lipase. These findings support the effectiveness of leveraging dipeptidyl peptidase IV inhibitor structures to design potent monoglyceride lipase inhibitors and suggest a promising therapeutic approach for improving insulin sensitivity and managing type 2 diabetes mellitus.