Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase

Fengtian Xue, Huiying Li, Silvia L. Delker, Jianguo Fang, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

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 Ki of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pKa 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.

Original languageEnglish (US)
Pages (from-to)14229-14238
Number of pages10
JournalJournal of the American Chemical Society
Volume132
Issue number40
DOIs
StatePublished - Oct 13 2010

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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