Bernhart C A, Perreaut P M, Ferrari B P, Muneaux Y A, Assens J L, Clément J, Haudricourt F, Muneaux C F, Taillades J E, Vignal M A
Sanofi Recherche, Montpellier, France.
J Med Chem. 1993 Oct 29;36(22):3371-80. doi: 10.1021/jm00074a018.
Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.
从新型非肽类血管紧张素Ⅱ 1型（AT1）受体拮抗剂DuP 753（氯沙坦）的结构出发，设计了一系列新的强效拮抗剂。在这些化合物中，中心咪唑核被二氢咪唑-4-酮结构所取代。活性最强的化合物在5位具有螺环戊烷或螺环己烷环。与咪唑系列一样，最佳取代基是1位的直链丁基和3位的[2'-（四氮唑-5-基）联苯基]甲基。通过化合物竞争性抑制[125I]血管紧张素Ⅱ与AT1亚型受体结合以及拮抗血管紧张素Ⅱ诱导的兔主动脉环收缩的能力来评估拮抗活性。活性最强的化合物的半数抑制浓度（IC50）值在纳摩尔范围内。在清醒大鼠中，化合物4和21口服给药时可拮抗血管紧张素Ⅱ的升压反应。化合物21（SR 47436）活性最强；最近的研究表明，它在食蟹猴中静脉注射和口服均有活性。该分子目前正在进行治疗高血压的临床试验。
