Pyrimidinyl Biphenylureas: Identification of New Lead Compounds as Allosteric Modulators of the Cannabinoid Receptor CB 1 .

The allosteric modulator 1-(4-chlorophenyl)-3-(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)phenyl)urea (PSNCBAM-1, 2) bound the cannabinoid receptor 1 (CB ₁ ) and antagonized G protein coupling. This compound demonstrated potent anorectic effects similar to the CB ₁ antagonist rimonabant that once was marketed for the treatment of obesity, suggesting a new chemical entity for the discovery of antiobesity drugs. To increase structural diversity of this class of CB ₁ ligands, we designed and synthesized two classes of novel analogues, in which the pyridine ring of 2 was replaced by a pyrimidine ring. These positively modulate the binding of the CB ₁ orthosteric agonist CP55,940 while exhibiting an antagonism of G-protein coupling activity. Interestingly, compounds 7d and 8d demonstrated ERK1/2 phosphorylation mediated via β-arrestin unlike the orthosteric CP55,940 that does so in a G protein-dependent manner. These can serve as new lead compounds for the future development of CB ₁ allosteric modulators that show biased agonism and potentially antiobesity behavior via a new mechanism.