Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2 R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 10; pp. 3037 - 3040
• Main Authors: Young, Robert J., Alderton, Wendy, Angell, Anthony D.R., Beswick, Paul J., Brown, David, Chambers, C. Lynn, Crowe, Miriam C., Dawson, John, Hamlett, Christopher C.F., Hodgson, Simon T., Kleanthous, Savvas, Knowles, Richard G., Russell, Linda J., Stocker, Richard, Woolven, James M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.05.2011; Elsevier
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Analytical, structural and metabolic biochemistry; Biological and medical sciences; endothelial nitric oxide synthase; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; glutamic acid; Heme - antagonists & inhibitors; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Humans; inducible nitric oxide synthase; Inhibitory Concentration 50; iron; Iron co-ordinating inhibitors; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; neuronal nitric oxide synthase; Nitric oxide synthase; Nitric Oxide Synthase Type II - antagonists & inhibitors; Oxidoreductases; Pharmacology. Drug treatments; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - chemistry; Proline - pharmacology; Iron co-ordinating inhibitors; Nitric oxide synthase; Human; Five membered ring; Enzyme; Nitrogen heterocycle; Nitric oxide synthase inhibitor; Isozyme; Enzyme inhibitor; Transition metal; Inhibitor enzyme complex; Selectivity; Modeling; Nitric-oxide synthase; Amidine; Structure activity relation; Molecular model; Oxidoreductases; Mechanism of action; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.03.038

The exploration of heterocyclic carboxamidines as iNOS inhibitors led to the identification of (2 R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor. Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2 R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC 50 = 0.12 μM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.