TOWARDS RATIONAL DEVELOPMENT OF PERIPHERALLY SELECTIVE ANTAGONISTS OF CANNABINOID RECEPTOR 1

Rangan Maitra, Alan Fulp, Katherine Bortoff, Herbert Seltzman, Yanan Zhang, Timothy Fennell, James Mathews, Rodney Snyder. RTI International, Discovery and Analytical Sciences, USA

Antagonists of cannabinoid receptor 1 (CB1R) have the potential for treating several important diseases such as drug addiction, obesity, diabetes, and liver disease. Unfortunately, adverse central nervous system (CNS)-related side effects including depression and suicidal ideation were reported with rimonabant (SR141716A), the first clinically approved CB1R antagonist (inverse agonist), leading to its withdrawal and the development of other CB1R antagonists were halted as well. However, CB1R is functionally expressed in peripheral organs and regulation of CB1R in these tissues by peripherally selective ligands is a promising approach to treat conditions like obesity, hepatic steatosis, and diabetes without eliciting the types of adverse effects noted with non-tissue selective agents. We have previously reported on the successful development of peripherally selective CB1R antagonists based on rimonabant (Bioorg Med Chem Lett. 21:5711-4; J Med Chem. 55:2820-34). Here we describe our efforts at developing peripherally selective CB1R antagonists that have a purine core, similar to otenabant (CP945598). These compounds were designed to have high topological polar surface areas (TPSA) because compounds with high TPSAs do not normally cross the blood brain barrier (BBB). Compounds were analyzed to determine their functional activity at CB1R using a calcium mobilization assay. Binding affinities and receptor selectivity of selected ligands were determined by radioligand displacement at CB1R and CB2R. Compounds with high TPSAs (TPSA>90), excellent functional activity (Ke ranging between 0.3-30 nM at CB1R), and high selectivity (>100-fold selective for CB1R versus CB2R) were identified. In vitro ADME profiling and testing in the MDCK-mdr1 model of BBB penetration led to the identification of compounds that were advanced into in vivo models to assess their CNS-permeability. Promising compounds were identified and they are currently undergoing further refinement and evaluation. In conclusion, we have developed highly potent and selective antagonists of the CB1R receptor that are under preclinical development to treat important indications like metabolic syndrome, diabetes, obesity, and liver disease.

Supported by 1R21AA019740-01 to R. Maitra from NIH.