Harnessing the pyrroloquinoxaline scaffold for FAAH and MAGL interaction: definition of the structural determinants for enzyme inhibition. Issue 69 (8th July 2016)

• Record Type: Journal Article
• Authors: Brindisi, Margherita; Brogi, Simone; Maramai, Samuele; Grillo, Alessandro; Borrelli, Giuseppe; Butini, Stefania; Novellino, Ettore; Allarà, Marco; Ligresti, Alessia; Campiani, Giuseppe; Di Marzo, Vincenzo; Gemma, Sandra
• Is Part Of: RSC advances. Volume 6:Issue 69(2016)
• Page Start: 64651
• Page End: 64664
• Publication Date: 2016-07-08
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6ra12524g
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : The pharmacogenic pyrroloquinoxaline scaffold has been exploited for developing piperazine and 4-aminopiperidine carboxamides/carbamates as inhibitors of the endocannabinoids' catabolic enzymes fatty acid amide hydrolase and monoacylglycerol lipase. Abstract : This paper describes the development of piperazine and 4-aminopiperidine carboxamides/carbamates supported on a pharmacogenic pyrroloquinoxaline scaffold as inhibitors of the endocannabinoid catabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Structure–activity relationships and molecular modelling studies allowed the definition of the structural requirements for dual FAAH/MAGL inhibition and led to the identification of a small set of derivatives (compounds5e, i, k, m ) displaying a balanced inhibitory profile against both enzymes, with compound5m being the frontrunner of the subset. Favorable calculated physico-chemical properties suggest further investigation for specific analogues.