3 research outputs found
Structure–Activity Relationship Development Efforts towards Peripherally Selective Analogs of the Cannabinoid Receptor Partial Agonist BAY 59-3074
Selective modulation of peripheral cannabinoid receptors (CBRs) has potential therapeutic applications in medical conditions, including obesity, diabetes, liver diseases, GI disorders and pain. While there have been considerable efforts to produce selective antagonists or full agonists of CBRs, there has been limited reports on the development of partial agonists. Partial agonists targeting peripheral CBRs may have desirable pharmacological profiles while not producing centrally mediated dissociative effects. Bayer reported that BAY 59-3074 is a CNS penetrant partial agonist of both CB1 and CB2 receptors with efficacy in rat models of neuropathic and inflammatory pain. In this report, we demonstrate our efforts to synthesize analogs that would favor peripheral selectivity, while maintaining partial agonism of CB1. Our efforts led to the identification of a novel compound, which is a partial agonist of the human CB1 (hCB1) receptor with vastly diminished brain exposure compared to BAY 59-3074
Blocking Alcoholic Steatosis in Mice with a Peripherally Restricted Purine Antagonist of the Type 1 Cannabinoid Receptor
Type
1 cannabinoid receptor (CB1) antagonists have demonstrated
promise for the treatment of obesity, liver disease, metabolic syndrome,
and dyslipidemias. However, the inhibition of CB1 receptors in the
central nervous system can produce adverse effects, including depression,
anxiety, and suicidal ideation. Efforts are now underway to produce
peripherally restricted CB1 antagonists to circumvent CNS-associated
undesirable effects. In this study, a series of analogues were explored
in which the 4-aminopiperidine group of compound <b>2</b> was
replaced with aryl- and heteroaryl-substituted piperazine groups both
with and without a spacer. This resulted in mildly basic, potent antagonists
of human CB1 (hCB1). The 2-chlorobenzyl piperazine, <b>25</b>, was found to be potent (<i>K</i><sub>i</sub> = 8 nM);
to be >1000-fold selective for hCB1 over hCB2; to have no hERG liability; and to possess favorable ADME properties including high oral absorption and negligible CNS penetration. Compound <b>25</b> was tested
in a mouse model of alcohol-induced liver steatosis and found to be
efficacious. Taken together, <b>25</b> represents an exciting
lead compound for further clinical development or refinement