Potent, Highly Selective, and Orally Bioavailable Gem-Difluorinated Monocationic Inhibitors of Neuronal Nitric Oxide Synthase

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• 作者：Fengtian Xue ; Huiying Li ; Silvia L. Delker ; Jianguo Fang ; Pavel Martsek ; Linda J. Roman ; Thomas L. Poulos ; Richard B. Silverman
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：October 13, 2010
• 年：2010
• 卷：132
• 期：40
• 页码：14229-14238
• 全文大小：416K
• 年卷期：v.132,no.40(October 13, 2010)
• ISSN：1520-5126

文摘

In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF₂ moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K_i of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK_a NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished.