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Biopterin-based inhibitors of nitric oxide synthase


Excessive NO causes tissue damage in diseases of unmet medical need such as stroke, arthritis and diabetes. Induction of Type II NOS contributes importantly to cytotoxicity and bystander damage in these pathological states. Current inhibitors are mainly arginine mimics and show limited selectivity for type II NOS over the constitutive Type I and Type III isoforms and have side effects. Synthesis of inhibitors of the binding of tetrahydrobiopterin, a cofactor requires by the enzyme, by means of non-pterin moieties which also bind haem to provide a possibly unique "selectivity signature" for NOS is proposed as a novel approach to selective NOS inhibition. Suitable leads are available in 7-nitroindazole and in phenylimidazole isomers, and data for pterins suggest that the tetrahydrobiopterin binding sites of the NOS isoforms may be distinguishable. In addition, because of its high level of expression, Type II NOS may be particularly susceptible to this form of inhibition.


SmithKline Beecham Pharmaceuticals Ltd.
Great West Road
TW8 9EP Brentford
United Kingdom

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