Mizuno A, Ogata A, Kamei T, Shibata M, Shimamoto T, Hayashi Y, Nakanishi K, Takiguchi C, Oka N, Inomata N
Suntory Institute for Biomedical Research, Mishima-gun, Osaka, Japan.
Chem Pharm Bull (Tokyo). 2000 May;48(5):623-35. 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-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 alpha1 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 thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.
合成了一系列5-氨基烷基吡咯并[3,2-c]氮杂卓衍生物，并评估了它们的5-羟色胺2（5-HT2）受体拮抗活性和抗血小板聚集活性。5-HT2受体拮抗活性很大程度上取决于吡咯并[3,2-c]氮杂卓环8位取代基的性质以及5位氨基烷基的性质。化合物18a，即5-[3-[4-(4-氟苯基)哌嗪-1-基]丙基]-8-羟基-1-甲基-1,4,5,6,7,8-六氢吡咯并[3,2-c]氮杂卓-4-酮，被认为具有强效的5-HT2受体拮抗活性，α1肾上腺素能受体阻断活性较弱，且对D2受体无明显结合亲和力，而相应的异构体吡咯并[3,4-c]氮杂卓衍生物（22）仅表现出较弱的5-HT2受体拮抗活性。外消旋的18a通过非对映体盐形成直接拆分后，对每个对映体进行了精确评估。发现18a的5-HT2受体拮抗活性主要存在于（-）-18a中（在分离的豚鼠动脉中，其效力比（+）-18a高约14倍）。因此，（S）-（-）-18a（SUN C5174）表现出总体最佳的特性，具有强效的5-HT2受体拮抗活性（pA2 = 8.98±0.06），且对其他受体具有高选择性。SUN C5174对犬或人富含血小板血浆中血清素与胶原蛋白和二磷酸腺苷（ADP）联合诱导的血小板聚集具有显著抑制作用（IC50 = 6.5至16 nM）。此外，该化合物在口服剂量为0.3 mg/kg或更高时，能显著抑制胶原蛋白和血清素诱导的小鼠急性肺血栓栓塞死亡的死亡率。SUN C5174目前正在进行临床评估。
