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Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor |
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| 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 |
| Institution: | GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK |
| Abstract: | Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC50 = 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. |
| Keywords: | Nitric oxide synthase Iron co-ordinating inhibitors |
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