Gómez-Vidal José A, Martásek Pavel, Roman Linda J, Silverman Richard B
Department of Chemistry, Drug Discovery Program, Northwestern University, Evanston, Illinois 60208-3113, USA.
J Med Chem. 2004 Jan 29;47(3):703-10. doi: 10.1021/jm030297m.
Selective inhibition of the isoforms of nitric oxide synthase (NOS) in pathologically elevated synthesis of nitric oxide has great therapeutic potential. We previously reported nitroarginine-containing dipeptide amides and some peptidomimetic analogues as potent and selective inhibitors of neuronal NOS (nNOS). Here we report conformationally restricted dipeptides derived from the dipeptide L-Arg(NO2)-L-Dbu-NH2 (8). The selectivities for nNOS over endothelial NOS and inducible NOS of the most potent nNOS inhibitor (10a) among these compounds are comparable to that of the parent compound. An unsubstituted amide bond is necessary for potency against nNOS. The stereochemistry of compound 10a was optimum for potency and selectivity and thus provides the binding conformation of the parent compound with nNOS.
在病理性一氧化氮合成升高的情况下，选择性抑制一氧化氮合酶（NOS）的亚型具有巨大的治疗潜力。我们之前报道了含硝基精氨酸的二肽酰胺和一些拟肽类似物作为神经元型一氧化氮合酶（nNOS）的强效和选择性抑制剂。在此我们报道了源自二肽L-Arg(NO2)-L-Dbu-NH2（8）的构象受限二肽。这些化合物中最有效的nNOS抑制剂（10a）对nNOS相对于内皮型一氧化氮合酶和诱导型一氧化氮合酶的选择性与母体化合物相当。未取代的酰胺键对于抗nNOS的效力是必需的。化合物10a的立体化学对于效力和选择性是最佳的，因此提供了母体化合物与nNOS的结合构象。
