1: J Med Chem. 2006 Feb 9;49(3):872-82. 

Synthesis and activity of 1,3,5-triphenylimidazolidine-2,4-diones and
1,3,5-triphenyl-2-thioxoimidazolidin-4-ones: characterization of new CB1
cannabinoid receptor inverse agonists/antagonists.

Muccioli GG, Wouters J, Charlier C, Scriba GK, Pizza T, Di Pace P, De Martino P,
Poppitz W, Poupaert JH, Lambert DM.

Unite de Chimie pharmaceutique et de Radiopharmacie, Ecole de Pharmacie, Faculte
de Medecine, Universite catholique de Louvain, Avenue E. Mounier 73, UCL-CMFA
7340, B-1200 Brussels, Belgium.

Obesity and metabolic syndrome, along with drug dependence (nicotine, alcohol,
opiates), are two of the major therapeutic applications for CB(1) cannabinoid
receptor antagonists and inverse agonists. In the present study, we report the
synthesis and structure-affinity relationships of
1,5-diphenylimidazolidine-2,4-dione and 1,3,5-triphenylimidazolidine-2,4-dione
derivatives. These new 1,3,5-triphenylimidazolidine-2,4-dione derivatives and
their thio isosteres were obtained by an original pathway and exhibited
interesting affinity and selectivity for the human CB(1) cannabinoid receptor. A
[(35)S]-GTPgammaS binding assay revealed the inverse agonist properties of the
compounds at the CB(1) cannabinoid receptor. Furthermore, molecular modeling
studies were conducted in order to delineate the binding mode of this series of
derivatives into the CB(1) cannabinoid receptor.
1,3-Bis(4-bromophenyl)-5-phenylimidazolidine-2,4-dione (25) and
1,3-bis(4-chlorophenyl)-5-phenylimidazolidine-2,4-dione (23) are the
imidazolidine-2,4-dione derivatives possessing the highest affinity for the
human CB(1) cannabinoid receptor reported to date.

PMID: 16451053 [PubMed - in process]