Stark H, Sadek B, Krause M, Hüls A, Ligneau X, Ganellin C R, Arrang J M, Schwartz J C, Schunack W
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
J Med Chem. 2000 Oct 19;43(21):3987-94. doi: 10.1021/jm000966l.
Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.
根据 Mitsunobu 反应或亲核芳香取代反应（S(N)Ar 反应）合成了具有 4-(3-(苯氧基)丙基)-1H-咪唑结构且通常在苯环对位有取代基的新型组胺 H(3)受体拮抗剂。通过体外和体内筛选 H(3)受体拮抗剂活性，羰基取代衍生物被证明是高活性化合物。许多化合物在体外表现出亚纳摩尔浓度范围内的亲和力，4-己酰基（10）和 4-乙酰基-3-甲基（29）取代衍生物在口服给药后体内拮抗剂活性约为 0.1 mg/kg。还测试了许多普罗西泮对其他组胺受体亚型的亲和力，从而证明了它们对 H(3)受体亚型的显著选择性。由于环丙基酮衍生物 14（西普罗芬）在体外具有高亲和力且在体内具有高效力，因此被选用于在猴子身上进行进一步研究。它显示出良好的口服吸收和持久的、剂量依赖性的血浆水平，使其成为药物开发的有前景的化合物。
