Nω-nitroarginine-containing dipeptide amides.: Potent and highly selective inhibitors of neuronal nitric oxide synthase
Nω-nitroarginine-containing dipeptide amides.: Potent and highly selective inhibitors of neuronal nitric oxide synthase
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DOI：
10.1021/jm990111c
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发表时间：
1999-08-12
影响因子：
7.3
通讯作者：
Silverman, RB
中科院分区：
文献类型：
--
作者：
Huang, H;Martasek, P;Silverman, RB
选择性抑制一氧化氮合酶（NOS）的同工异构体在治疗由一氧化氮（NO）过量产生引起的某些疾病状态方面可能是有用的。最近，我们报道了二肽甲酯，d - ph - d - arg (NO2)-OMe(19)，作为一种适度的nNOS抑制剂（K-i = 2 μ M），但对iNOS的选择性高达1800倍（Silverman， R. B.; Huang， H.; Marletta， M. a .; Martasek， P. J. Med. Chem. 1997, 40, 2813-2817）。本文合成了152种含硝基精氨酸和非苯丙氨酸的二肽酰胺，并对其活性进行了筛选。含有碱性胺侧链的二肽酰胺对eNOS和iNOS具有良好的抑制效能和选择性（20-24），这表明在酶活性位点可能存在静电（或氢键）相互作用。其中，L-Arg(NO2)- l - dbus - nh2 (23) （K-i = 130 nM）对eNOS的选择性最高，达到1500倍，对iNOS的选择性为192倍。这些化合物不表现出时间依赖性的抑制作用。二肽酰胺中氨基酸的顺序和手性对抑制效果和同工异构体的选择性有深远的影响。这些二肽酰胺抑制剂为设计强效和高选择性的nNOS抑制剂打开了大门。
Selective inhibition of the isoforms of nitric oxide synthase (NOS) could be therapeutically useful in the treatment of certain disease states arising from the overproduction of nitric oxide (NO). Recently, we reported the dipeptide methyl ester, D-Phe-D-Arg(NO2)-OMe (19), as a modest inhibitor of nNOS (K-i = 2 mu M), but with selectivity over iNOS as high as 1800-fold (Silverman, R. B.; Huang, H.; Marletta, M. A.; Martasek, P. J. Med. Chem. 1997, 40, 2813-2817). Here a library of 152 dipeptide amides containing nitroarginine and amino acids other than Phe are synthesized and screened for activity. Excellent inhibitory potency and selectivity for nNOS over eNOS and iNOS is achieved with the dipeptide amides containing a basic amine side chain (20-24), which indicates a possible electrostatic (or hydrogen bonding) interaction at the enzyme active site. The most potent nNOS inhibitor among these compounds is L-Arg(NO2)-L-Dbu-NH2 (23) (K-i = 130 nM), which also exhibits the highest selectivity over eNOS (>1500-fold) with a 192-fold selectivity over iNOS. These compounds do not exhibit time-dependent inhibition. The order and the chirality of the amino acids in the dipeptide amides have profound influences on the inhibitory potency as well as on the isoform selectivity. These dipeptide amide inhibitors open the door to the design of potent and highly selective inhibitors of nNOS.