Rimonabant

Rimonabant is the first-in class CB1 receptor antagonist, which has recently reached the market in Europe (approval in the US is pending). The reduction of... 

Endocannabinoids. Figure 1 Chemical structures of the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, of Cannabis sativa psychoactive principle, A9-tetrahydrocannabinol, and of the CB-i receptor antagonist/inverse agonist, rimonabant. 

In recent years pre-clinical testing and, in particular, clinical data on SR141716A (Rimonabant, Acomplia) (382) from Sanofi-Aventis (previously... 

The most important class of CBi receptor antagonists identified to date are the 1,5-diaryl-pyrazoles. This class includes rimonabant (382), first described in patent applications from Sanofi just over a decade ago [263, 264]. Rimonabant has proved invaluable in the elucidation of carmabinoid receptor pharmacology, as described in the section on therapeutic applications below. 

The biological activity of the compounds was assessed in two binding assays using [ H]-CP 55,940 (see Table 6.36) and [ H]-rimonabant (data not shown), and their functional activity determined using a GTPyS assay. Upon... 

Table 6.36 MODIFIED AMIDE SUBSTITUENT ANALOGUES OF RIMONABANT...

CoMFA has also been used by Shim and co-workers [279] to help understand the interaction between rimonabant (382) and the CBi receptor. 

Table 6.38 PYRAZOLINE DERIVATIVES AND RIMONABANT (382) - IN VIVO DATA...

A thiazole core has also been utilised by Solvay Pharmaceuticals [309] in the search for a novel bioisosterie replacement of the rimonabant (382) pyrazole core. The affinity of several compounds for the human CBi receptor was determined in transfected CHO cells using tritium-labelled CP 55940. Antagonism was determined in the same cell line by WIN 55212-2-induced release of arachidonic acid. The pK[ of (456) was found to be 6.9, while the p 2 value was measured as 8.7. A series of six 1,2,4-triazole analogues has been prepared by Jagerovic et al. [310], via their corresponding A-acylbenzamides (Table 6.39). 

Table 6.40 THIAZOLE- AND TRIAZOLE-BASED BIOISOSTERES OF RIMONABANT (382) -/JV VITRO DATA [311]...

The CBi functional activity of a number of the imidazole-based compounds reported exceeds that measured for rimonabant (382) (Table 6.43). While marked CB1/CB2 selectivity is witnessed throughout the series, the selectivity of direct (382) analogue (470) was found to be approximately 3-fold lower than for (382) itself (Table 6.44). 

The trichloro derivative corresponding most closely to rimonabant (382), (496) was found to have excellent CBi affinity (IC50 = 6.1 nM) cf. (382) ... 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

Our current understanding of the potential therapeutic applications of CBi antagonists owes a great deal to the discovery of rimonabant (382). Indeed, clinical data demonstrating the efficacy of (382) in the treatment of obesity and nicotine addiction has provided a substantial driving force for the expanding research effort into this approach. 

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