Cannabinoid CB₁ receptor antagonists in therapeutic and structural perspectives

Abstract

The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 receptor antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 receptor antagonist structure classes.

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

“…Several comprehensive reviews have been published, which summarize the effects of replacing substituents in the 1,5-diaryl group or in 3-carboxamide moiety of rimonabant with different amines and the central pyrazole skeleton with analogous heteroaromatic rings [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Studies have shown that the thiophene ring is a drug-like, bioisostere of a phenyl ring [62].…”

“…During the approximately 15 year period after the first publication of studies with rimonabant, a significant number of new chemical CB 1 R blockers were uncovered and a number of reviews dealing with these cannabinoid ligands have been published [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32].…”

Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach

“…CB 1 receptor is mainly expressed in the central nervous system where it controls motivation for appetitive stimuli, including food and drugs. Currently, CB 1 antagonists and inverse agonists are evaluated for obesity, metabolic disorders, smoking cessation, and alcohol abuse [4][5][6].…”

Cannabinoid receptor ligands as potential anticancer agents — high hopes for new therapies?

“…CB 1 receptor antagonists also have good prospects in other therapeutic areas, including smoking cessation, alcohol addiction and cognitive impairment. [21] CB 1 agonists are useful for the prevention of nausea and vomiting and to stimulate appetite. [22] There is increasing evidence that CB receptors are involved in numerous immune mechanisms and are generally able to attenuate inflammatory processes.…”

“…[39] Different selective and non-selective CB 1 /CB 2 receptor ligands have been described, which show potential for a wide range of diseases. [20,21] Evidence accumulated within the last decade suggests that CB receptor agonists may have antitumour properties in a variety of cancer types; this topic has been reviewed in several cancer-related journals. [40][41][42][43] In this review, the recent developments and insights are discussed with respect to CB receptor signalling, ligand selectivity, specificity of effect in different tissues and potential therapeutic relevance.…”