Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-amino)ethylamino]pentyl}-N′-nitroguanidine (l-Arg(NO2)-l-Dbu-NH2 (1) and 4-N-(Nω-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), a series of descarboxamide analogues was designed and synthesized (3–7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. Nα-Methylated analogues (8–11) also were prepared for increased lipophilicity of the inhibitors, but they had 4- to 5-fold weaker binding affinity compared to their parent compounds.

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