Design and Synthesis of trans-3-(2-(4-(3-(5-Methyl-1,2,4-oxadiazolyl))-phenyl)carboamido)cyclohexyl)ethyl)-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SB-414796): A Potent and Selective Dopamine D_3 Receptor Antagonist

摘要

At their clinical doses, current antipsychotic agents share the property of both dopamine D_2 and D_3 receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D_2 receptor antagonism. Consequently, a selective dopamine D_3 receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D_3 receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzaepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzacepines has been prepared. Compounds of this type combined a high level of D-3 affinity and selectivity vs D_2 with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl)phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D_3 receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have at role in the treatment of cue-induced relapse in drug-free cocaine addicts.