Substituted pyrimidines as cannabinoid CB1 receptor ligands

Cannabinoid CB1 receptors have been the avenue of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of substituted pyrimidines based on chemical structure of Merck’s taranabant, a cannabinoid CB1 receptor inverse agonist. Noticeably, N4-((2S,3S)-3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-yl)-N6-butylpyrimidine-4,6-diamine (13b) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC50 = 16.3 nM, CB2/CB1 = 181.6).

Graphical abstractWe have identified novel substituted pyrimidine series of small molecule cannabinoid-1 ligands that exhibited decent CB1 receptor binding affinities. Among various analogues, N-butylaminopyrimidine (13b) demonstrated favorable binding affinity for CB1 receptor.Figure optionsDownload full-size imageDownload as PowerPoint slide