Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives
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- 作者：Haitao Ji ; Silvia L. Delker ; Huiying Li ; Pavel Martsek ; Linda J. Roman ; Thomas L. Poulos ; Richard B. Silverman
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：November 11, 2010
- 年：2010
- 卷：53
- 期：21
- 页码：7804-7824
- 全文大小：1448K
- 年卷期：v.53,no.21(November 11, 2010)
- ISSN：1520-4804
文摘
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8−34) was designed and synthesized. A structure−activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3′-[2′′-(3′′′-fluorophenethylamino)ethoxy]pyrrolidin-4′-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3′R,4′R)-4 can induce enzyme elasticity to generate a new “hot spot” for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3′R,4′R)-3′-[2′′-(3′′′-fluorophenethylamino)ethylamino]pyrrolidin-4′-yl}methyl}-4-methylpyridin-2-amine ((3′R,4′R)-3) ( J. Am. Chem. Soc. 2010, 132 (15), 5437−5442). On the basis of structure−activity relationships of 8−34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.