Nilsson Jonas W, Kvarnström Ingemar, Musil Djordje, Nilsson Ingemar, Samulesson Bertil
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
J Med Chem. 2003 Sep 11;46(19):3985-4001. doi: 10.1021/jm0307990.
A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in D-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of alpha-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 microM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with alpha-thrombin is discussed.
一种源自苹果酸的4-氨基-2-羧甲基-3-吗啉酮结构基序已被用于模拟凝血酶抑制三肽d-Phe-Pro-Arg中的d-Phe-Pro。D-Phe-Pro-Arg中的精氨酸被刚性更强的P1截短对脒基苄胺（Pab）取代。这些新型凝血酶抑制剂被用于探究α-凝血酶的抑制剂结合位点。该系列凝血酶抑制剂中的最佳候选物在体外的IC50为0.130微摩尔。有趣的是，与先前报道的2-羧甲基-3-吗啉酮系列相比，最具活性的化合物中4-氨基-2-羧甲基-3-吗啉酮基序的立体化学发生了反转。讨论了先导抑制剂与α-凝血酶共结晶的X射线晶体结构。
