Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5- aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds

Article abstract of DOI:10.1248/cpb.48.623

A series of 5-aminoalkylpyrrolo[3,2,c]azepine derivatives was synthesized and their serotonin 2 (5-HT₂) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT₂ receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-(4- fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5,6,7,8- hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT₂ receptor antagonist activity with weak α₁ adrenoceptor blocking activity and no significant D₂ receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT₂ receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT₂ receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174)displayed the overall best profile with potent 5-HT₂ receptor antagonist activity (pA₂ = 8.98 ± 0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC₅₀ = 6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolitic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.

Full text of DOI:10.1248/cpb.48.623

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