The most widely studied compound of the diarylpyrazole class is SR141716A (Rimonabant) (59, Fig. 7), developed by Rinaldi-Carmona and coworkers at Sanofi, which has passed phase III clinical trials for the treatment of obesity and smoking cessation (69). This highly potent and selective CBi receptor ligand has served as a unique pharmacological and biochemical tool for further characterization of the CB1 receptor (70,71). Other diarylpyrazole ligands that have contributed to our understanding of CB1 pharmacology are AM251 and AM281 (60 and 61, respectively, Fig. 7). Both AM251 and AM281 are CB1 antagonist/inverse agonists capable of displacing [3H]SR141716A and [3H]CP-55,940 in CB1 receptor membrane preparations and share the ability of SR141716A to attenuate the responses to established cannabinoid receptor agonists like WIN55,212-2 or CP-55,940. However, recent evidence indicates that AM251 may have a more "CB ^selective" role than SR141716A. The most notable CB2 receptor antagonist/inverse agonist is SR144528, a diarylpyrazole (62, Fig. 7) developed by Sanofi, exhibiting 700-fold selectivity for the CB2 receptor over CB1.
The synthesis of AM281 [N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1#-pyrazole-3-carboxamide] (61) is outlined in Scheme 15. 4'-Bromopropiophenone was reacted with diethyl oxalate in anhydrous diethyl ether under basic conditions to afford the lithium salt of ethyl 2,4-dioxo-3-methyl-4-(4-bromophenyl) butanoate 63, which was further reacted with 2,4-
Fig. 7. Representative diarylpyrazole ligands.
dichlorophenylhydrazine hydrochloride to provide 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1#-pyrazole-3-carboxylic acid ethyl ester 64. The procedure (see also ref. 72) for the conversion of ester 64 to amide 65 via three steps analogously to the synthesis of AM251 (73) was now shortened to a single step in which ester 64 was allowed to react with 4-aminomorpholine under basic conditions (74). Subsequently, the bromo derivative 65 reacted with bis(tributyltin) in the presence of a catalytic amount of tetrakis(triphenylphos-phine)palladium to afford the tributyltin derivative 66. Iododestannylation of compound 66 using iodine in a carbon tetrachloride solution gave AM281 (61) in almost quantitative yield.
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