Amberg W, Hergenröder S, Hillen H, Jansen R, Kettschau G, Kling A, Klinge D, Raschack M, Riechers H, Unger L
Hauptlaboratorium, BASF AG, 67056 Ludwigshafen, Germany, and Knoll AG, 67008 Ludwigshafen, Germany.
J Med Chem. 1999 Aug 12;42(16):3026-32. doi: 10.1021/jm9910425.
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.
内皮素A选择性拮抗剂（S）-3-甲氧基-2-（4,6-二甲氧基嘧啶-2-基氧基）-3,3-二苯基丙酸（LU 135252）的结构变异产生了一些类似物，这些类似物保留了对ET(A)的亲和力，但也表现出相当程度的对ET(B)的亲和力。得到的活性最高的衍生物是（S）-3-[2-（3,4-二甲氧基苯基）乙氧基]-2-（4,6-二甲基嘧啶-2-基氧基）-3,3-二苯基丙酸（LU 302872），它可以通过酸催化的转醚化反应经八步以对映体纯的形式制备。它与ET(A)受体结合的K(i) = 2.15 nM，与ET(B)受体结合的K(i) = 4.75 nM，口服有效，并且每次以10 mg/kg的剂量拮抗大鼠体内大内皮素诱导的血压升高和豚鼠体内大内皮素诱导的支气管痉挛。
