Tulshian D, Czarniecki M, Doll R J, Ahn H S
Schering-Plough Research Institute, Kenilworth, New Jersey 07033.
J Med Chem. 1993 Apr 30;36(9):1210-20. doi: 10.1021/jm00061a012.
Synthetic analogs of the natural product griseolic acid in which a guanine base is substituted for the adenine have been prepared. The best of these compounds inhibits a cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase preparation with an IC50 of 0.34 microM but is a very weak inhibitor of a cyclic adenosine 3',5'-monophosphate (cAMP) phosphodiesterase. An exploration of stereochemistry indicates that the configuration of the carboxylic acids and the ring fusion in the inhibitors is important for potent cGMP PDE inhibition. PDE inhibition is not sensitive to the presence of the 2' or 4' oxygen atoms in the ribose, but inhibition is decreased when the 3' oxygen is removed. A selected group of analogs in which a monocarboxylic acid is present are poor inhibitors. The structure-activity relationship is consistent with the carboxylic acid functionality acting as a mimetic for the phosphate anion in cGMP. This concept is supported by a conformational analysis of two of the inhibitors.
已经制备了天然产物灰黄霉素酸的合成类似物，其中鸟嘌呤碱基取代了腺嘌呤。这些化合物中最好的一种抑制环鸟苷3',5'-单磷酸（cGMP）磷酸二酯酶制剂，IC50为0.34微摩尔，但对环腺苷3',5'-单磷酸（cAMP）磷酸二酯酶的抑制作用非常弱。立体化学研究表明，抑制剂中羧酸的构型和环稠合对于有效的cGMP PDE抑制很重要。PDE抑制对核糖中2'或4'氧原子的存在不敏感，但当3'氧被去除时抑制作用会降低。一组存在单羧酸的选定类似物是较差的抑制剂。构效关系与羧酸官能团作为cGMP中磷酸根阴离子的模拟物的作用一致。这一概念得到了两种抑制剂的构象分析的支持。
