Selective L-nitroargininylaminopyrrolidine and L-nitroargininylaminopiperidine Neuronal Nitric Oxide Synthase Inhibitors

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2007 Jan 24

PMID 17239601

Citations 9

Authors

Jiwon Seo

Pavel Martasek

Linda J Roman

Richard B Silverman

Affiliations

Soon will be listed here.

Abstract

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-(Nomega-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. Nalpha-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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