Nakane M, Klinghofer V, Kuk J E, Donnelly J L, Budzik G P, Pollock J S, Basha F, Carter G W
Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Mol Pharmacol. 1995 Apr;47(4):831-4.
We have identified two novel potent and selective inhibitors of inducible nitric oxide synthase, S-ethylisothiourea and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. Ki values of 14.7 nM for S-ethylisothiourea and 4.2 nM for 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine were obtained with partially purified preparations of inducible nitric oxide synthase. These compounds demonstrate about 1000-fold greater potency than prototypical inhibitors, and the inhibitions are 10-40-fold more selective for murine inducible nitric oxide synthase, compared with the rat neuronal and bovine endothelial isoforms of nitric oxide synthase. These compounds also potently inhibit the nitric oxide synthase activity in intact J774 mouse macrophages. The inhibition is competitive with the substrate L-arginine and reversible in both enzymatic and intact cell assays. These potent and selective inhibitors of inducible nitric oxide synthase may have potential therapeutic applications in the treatment of inflammatory and autoimmune diseases.
我们已经鉴定出两种新型的诱导型一氧化氮合酶强效选择性抑制剂，即S-乙基异硫脲和2-氨基-5,6-二氢-6-甲基-4H-1,3-噻嗪。使用部分纯化的诱导型一氧化氮合酶制剂，测得S-乙基异硫脲的Ki值为14.7 nM，2-氨基-5,6-二氢-6-甲基-4H-1,3-噻嗪的Ki值为4.2 nM。这些化合物的效力比典型抑制剂高约1000倍，与大鼠神经元型和牛内皮型一氧化氮合酶相比，对小鼠诱导型一氧化氮合酶的抑制选择性高10至40倍。这些化合物还能有效抑制完整J774小鼠巨噬细胞中的一氧化氮合酶活性。这种抑制作用与底物L-精氨酸具有竞争性，并且在酶促和完整细胞试验中都是可逆的。这些诱导型一氧化氮合酶的强效选择性抑制剂可能在炎症和自身免疫性疾病的治疗中具有潜在的治疗应用。
