Garvey E P, Oplinger J A, Tanoury G J, Sherman P A, Fowler M, Marshall S, Harmon M F, Paith J E, Furfine E S
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
J Biol Chem. 1994 Oct 28;269(43):26669-76.
S-Ethylisothiourea was a potent competitive inhibitor of human nitric oxide synthase (NOS), with Ki values of 17, 36, and 29 nM for the inducible (i), endothelial (e), and neuronal (n) isozymes, respectively. Unlike some potent inhibitors of NOS, no time dependence was observed. S-Ethylisothiourea was not a detectable substrate for eNOS. S-Ethylisothiourea was also a potent inhibitor of mouse iNOS (Ki value of 5.2 nM), and its binding perturbed the spectrum of iNOS consistent with its altering the environment of the bound heme. The optimum binding of S-ethyl- and S-isopropylisothiourea relative to 70 other analogs suggested that these alkyl substitutions fit into a small hydrophobic pocket. Most isothioureas were 2-6-fold selective for the human iNOS (Ki for iNOS versus Ki for eNOS), with one being 19-fold selective. The cyclized mimics of S-ethylisothiourea, 2-NH2-thiazoline, and 2-NH2-thiazole, were also competitive inhibitors of human NOS. A third structural class of inhibitors, bisisothioureas, were, in general, the most selective in their inhibition of human iNOS. S,S'-(1,3-Phenylenebis(1,2-ethanediyl))bisisothiourea was 190-fold selective (Ki value of 0.047 microM against iNOS versus 9.0 microM against eNOS). These results demonstrate that potent and selective inhibition of human NOS isozymes is achievable.
S - 乙基异硫脲是一种强效的人一氧化氮合酶（NOS）竞争性抑制剂，对诱导型（i）、内皮型（e）和神经元型（n）同工酶的Ki值分别为17、36和29 nM。与一些强效的NOS抑制剂不同，未观察到时间依赖性。S - 乙基异硫脲不是可检测到的内皮型一氧化氮合酶（eNOS）底物。S - 乙基异硫脲也是小鼠诱导型一氧化氮合酶（iNOS）的强效抑制剂（Ki值为5.2 nM），其结合使iNOS的光谱发生扰动，这与其改变结合血红素的环境一致。相对于其他70种类似物，S - 乙基和S - 异丙基异硫脲的最佳结合表明这些烷基取代基适合一个小的疏水口袋。大多数异硫脲对人诱导型一氧化氮合酶具有2 - 6倍的选择性（诱导型一氧化氮合酶的Ki值与内皮型一氧化氮合酶的Ki值相比），其中一种具有19倍的选择性。S - 乙基异硫脲的环化模拟物2 - NH₂ - 噻唑啉和2 - NH₂ - 噻唑也是人一氧化氮合酶的竞争性抑制剂。第三类结构抑制剂双异硫脲通常在抑制人诱导型一氧化氮合酶方面最具选择性。S,S' - (1,3 - 亚苯基双(1,2 - 乙二基))双异硫脲具有190倍的选择性（对诱导型一氧化氮合酶的Ki值为0.047 μM，对内皮型一氧化氮合酶的Ki值为9.0 μM）。这些结果表明，可以实现对人一氧化氮合酶同工酶的强效和选择性抑制。
