Niwata S, Fukami H, Sumida M, Ito A, Kakutani S, Saitoh M, Suzuki K, Imoto M, Shibata H, Imajo S, Kiso Y, Tanaka T, Nakazato H, Ishihara T, Takai S, Yamamoto D, Shiota N, Miyazaki M, Okunishi H, Kinoshita A, Urata H, Arakawa K
Institute for Biomedical Research, Suntory Ltd., Osaka, Japan.
J Med Chem. 1997 Jul 4;40(14):2156-63. doi: 10.1021/jm960793t.
A series of 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives have been synthesized and evaluated for their ability to selectively inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The 1-phenyl moiety participates in a hydrophobic interaction where an optimum size is required. At this position, 3,4-dimethylphenyl is the best moiety for inhibiting chymase and showed high selectivity compared with chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrogen-bond acceptors such as nitrile and methoxycarbonyl enhances its activity. Molecular-modeling studies on the interaction of 3-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-imidazolidine-2,4-dione (29) with the active site of human heart chymase suggested that the 1-phenyl moiety interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, and the 4-carbonyl of the imidazolidine ring and sulfonyl group interact with the oxyanion hole and the His-45 side chain of chymase, respectively. The complex model is consistent with the structure-activity relationships.
已经合成了一系列3-(苯磺酰基)-1-苯基咪唑烷-2,4-二酮衍生物，并对其选择性抑制人心脏糜酶的能力进行了评估。对这些化合物的构效关系研究得出了以下结果。1-苯基部分参与疏水相互作用，在此需要一个最佳尺寸。在这个位置，3,4-二甲基苯基是抑制糜酶的最佳部分，与胰凝乳蛋白酶和组织蛋白酶G相比显示出高选择性。被诸如腈和甲氧基羰基等氢键受体取代的3-苯磺酰基部分增强了其活性。对3-[(4-氯苯基)磺酰基]-1-(4-氯苯基)-咪唑烷-2,4-二酮(29)与人心脏糜酶活性位点相互作用的分子模拟研究表明，1-苯基部分与疏水的P1口袋相互作用，3-苯磺酰基部分位于S1'-S2'亚位点，咪唑烷环的4-羰基和磺酰基分别与糜酶的氧负离子洞和His-45侧链相互作用。该复合物模型与构效关系一致。
