2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution

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

doi:10.1021/jm031035n

2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution

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

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	3320-3323
Number of pages	4
Journal	Journal of Medicinal Chemistry
Volume	47
Issue number	12
DOIs	https://doi.org/10.1021/jm031035n
State	Published - Jun 3 2004
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Connolly, S., Aberg, A., Arvai, A., Beaton, H. G., Cheshire, D. R., Cook, A. R., Cooper, S., Cox, D., Hamley, P., Mallinder, P., Millichip, I., Nicholls, D. J., Rosenfeld, R. J., St.-Gallay, S. A., Tainer, J., Tinker, A. C., & Wallace, A. V. (2004). 2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution. Journal of Medicinal Chemistry, 47(12), 3320-3323. https://doi.org/10.1021/jm031035n

Connolly, S, Aberg, A, Arvai, A, Beaton, HG, Cheshire, DR, Cook, AR, Cooper, S, Cox, D, Hamley, P, Mallinder, P, Millichip, I, Nicholls, DJ, Rosenfeld, RJ, St.-Gallay, SA, Tainer, J, Tinker, AC & Wallace, AV 2004, '2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution', Journal of Medicinal Chemistry, vol. 47, no. 12, pp. 3320-3323. https://doi.org/10.1021/jm031035n

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title = "2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution",

abstract = "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.",

author = "Stephen Connolly and Anders Aberg and Andrew Arvai and Beaton, {Haydn G.} and Cheshire, {David R.} and Cook, {Anthony R.} and Sally Cooper and David Cox and Peter Hamley and Phil Mallinder and Ian Millichip and Nicholls, {David J.} and Rosenfeld, {Robin J.} and St.-Gallay, {Stephen A.} and John Tainer and Tinker, {Alan C.} and Wallace, {Alan V.}",

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doi = "10.1021/jm031035n",

language = "English (US)",

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T1 - 2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution

AU - Connolly, Stephen

AU - Aberg, Anders

AU - Arvai, Andrew

AU - Beaton, Haydn G.

AU - Cheshire, David R.

AU - Cook, Anthony R.

AU - Cooper, Sally

AU - Cox, David

AU - Hamley, Peter

AU - Mallinder, Phil

AU - Millichip, Ian

AU - Nicholls, David J.

AU - Rosenfeld, Robin J.

AU - St.-Gallay, Stephen A.

AU - Tainer, John

AU - Tinker, Alan C.

AU - Wallace, Alan V.

PY - 2004/6/3

Y1 - 2004/6/3

N2 - 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.

AB - 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.

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2-Aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution

Abstract

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