1. J Med Chem. 2009 Dec 10;52(23):7410-20.

Synthesis and in vitro evaluation of N-substituted maleimide derivatives as
selective monoglyceride lipase inhibitors.

Matuszak N, Muccioli GG, Labar G, Lambert DM.

Faculté de Medecine, Unité de Chimie Pharmaceutique et de Radiopharmacie, Louvain
Drug Research Institute, Ecole de Pharmacie, Drug Design and Discovery Centre,
Université Catholique de Louvain, B-1200 Bruxelles, Belgium.

The endocannabinoid 2-arachidonoylglycerol (2-AG) plays a major role in many
physiological processes, and its action is quickly terminated via enzymatic
hydrolysis catalyzed by monoglyceride lipase (MGL). Regulating its endogenous
level could offer therapeutic opportunities; however, few selective MGL
inhibitors have been described so far. Here, we describe the synthesis of
N-substituted maleimides and their pharmacological evaluation on the recombinant 
human fatty acid amide hydrolase (FAAH) and on the purified human MGL. A few
N-arylmaleimides were previously described ( Saario , S. M. ; Salo , O. M. ;
Nevalainen , T. ; Poso , A. ; Laitinen , J. T. ; Jarvinen , T. ; Niemi , R.
Characterization of the Sulfhydryl-Sensitive Site in the Enzyme Responsible for
Hydrolysis of 2-Arachidonoylglycerol in Rat Cerebellar Membranes . Chem. Biol.
2005 , 12 , 649 - 656 ) as MGL inhibitors, and along these lines, we present a
new set of maleimide derivatives that showed low micromolar IC(50) and high
selectivity toward MGL vs FAAH. Then, structure-activity relationships have been 
investigated and, for instance, 1-biphenyl-4-ylmethylmaleimide inhibits MGL with 
an IC(50) value of 790 nM. Furthermore, rapid dilution experiments reveal that
these compounds act as irreversible inhibitors. In conclusion, N-substituted
maleimides constitute a promising class of potent and selective MGL inhibitors.

PMID: 19583260 [PubMed - indexed for MEDLINE]