title: Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo[3,2-c]azepines and related compounds.
abstract: 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.
authors.affiliation: Suntory Institute for Biomedical Research, Mishima-gun, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Mizuno
authors.forename: A
authors.initials: A
authors.lastname: Ogata
authors.forename: T
authors.initials: T
authors.lastname: Kamei
authors.forename: M
authors.initials: M
authors.lastname: Shibata
authors.forename: T
authors.initials: T
authors.lastname: Shimamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Nakanishi
authors.forename: C
authors.initials: C
authors.lastname: Takiguchi
authors.forename: N
authors.initials: N
authors.lastname: Oka
authors.forename: N
authors.initials: N
authors.lastname: Inomata
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D065127:Dopamine D2 Receptor Antagonists; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013923:Thromboembolism / Q000517:prevention & control
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D011943:Receptors, Adrenergic, beta; D017448:Receptors, Dopamine D2; D011970:Receptors, Histamine H2; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists