G. Amato, Amruta Manke, R. Wiethe
Jun 11, 2019
Citations
0
Influential Citations
10
Citations
Journal
Journal of medicinal chemistry
Abstract
Antagonists of peripheral type 1 cannabinoid receptors (CB1) have potential utility in the treatment of various diseases including metabolic syndrome, diabetes, liver diseases, fibrosis and gastrointestinal disorders. Unfortunately, inhibition of CB1 receptors in the central nervous system (CNS) produces adverse effects including depression, anxiety and suicidal ideation. Otenabant (1) is a potent and selective CB1 inverse agonist developed by Pfizer, but its advancement in clinical trials was halted because of its ability to penetrate the CNS and produce effects like rimonabant (2), a clinically approved drug that was eventually withdrawn. Structure-activity relationship (SAR) studies of 1 would be useful in developing analogs that have limited brain penetration and thereby, limited adverse effects. Recent crystal structures of hCB1 and docking studies with 1 indicate that the piperidine group could be functionalized at the 4-position to access a binding pocket that can accommodate both polar and nonpolar groups. In this publication, the piperidine is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a urea connector. Heterocyclic replacements for the 4-chlorophenyl group were also explored. These studies resulted in orally bioavailable and peripherally selective compounds that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. The lead compound 38 blocked alcohol-induced liver steatosis in mice.