Synthesis and Serotonin 2 (5-HT2) Receptor Antagonist Activity of 5-Aminoalkyl-Substituted Pyrrolo[3, 2-c]azepines and Related Compounds

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 5; pp. 623 - 635
• Main Authors: MIZUNO, Akira, OGATA, Atsto, KAMEI, Tomoe, SHIBATA, Makoto, SHIMAMOTO, Tetsuo, HAYASHI, Yasuhiro, NAKANISHI, Kyoko, TAKIGUCHI, Chikako, OKA, Naomi, INOMATA, Norio
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.05.2000; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: Adrenergic alpha-2 Receptor Antagonists; Animals; antiplatelet aggregation; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Crystallography, X-Ray; Dogs; Dopamine D2 Receptor Antagonists; Guinea Pigs; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - pharmacology; Pyrroles - chemical synthesis; Pyrroles - metabolism; Pyrroles - pharmacology; pyrrolo[3, 2-c]azepine; Rats; Receptors, Adrenergic, beta - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, Histamine H2 - drug effects; Receptors, Muscarinic - drug effects; Receptors, Serotonin - drug effects; Science & Technology; serotonin 2 receptor antagonist; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology; Spectrophotometry, Infrared; Structure-Activity Relationship; SUN C5174; Thromboembolism - prevention & control; ORGANIC-SYNTHESIS; PLATELET-AGGREGATION; SUNC5174; pyrrolo[3,2-c]azepine; antiplatelet aggregation; MECHANICAL-PROPERTIES; VASCULAR SMOOTH-MUSCLE; CORONARY-ARTERIES; BLOCKING-AGENT; MAMMALIAN BRAIN; 5-HT2-RECEPTOR ANTAGONIST; RAT-BRAIN; BINDING-SITES; serotonin 2 receptor antagonist; Enantioselectivity; Nitrogen heterocycle; Lactam; Cardiovascular disease; Anticoagulant; Selectivity; Prevention; Guinea pig; Structure activity relation; Bicyclic compound; Aorta; Antagonist; Chemical synthesis; Dog; Human; Fissipedia; Carnivora; Respiratory disease; Rodentia; Oral administration; In vitro; Artery; Antiplatelet agent; 5-HT2 Serotonine receptor; Pulmonary embolism; In vivo; Vertebrata; Experimental disease; Mammalia; Mouse; Animal; Affinity
• ISSN: 0009-2363; 1347-5223
• 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 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 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.