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2-Aminopyridines as Highly Selective Inducible Nitric Oxide Synthase Inhibitors. Differential Binding Modes Dependent on Nitrogen Substitution

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journal contribution
posted on 03.06.2004, 00:00 by Stephen Connolly, Anders Aberg, Andrew Arvai, Haydn G. Beaton, David R. Cheshire, Anthony R. Cook, Sally Cooper, David Cox, Peter Hamley, Phil Mallinder, Ian Millichip, David J. Nicholls, Robin J. Rosenfeld, Stephen A. St-Gallay, John Tainer, Alan C. Tinker, Alan V. Wallace
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.