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

Jiwon Seo; Pavel Martásek; Linda J. Roman; Richard B. Silverman

doi:10.1016/j.bmc.2007.01.001

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

Jiwon Seo, Pavel Martásek, Linda J. Roman, Richard B. Silverman^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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-(N^ω-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. N^α-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.

Original language	English (US)
Pages (from-to)	1928-1938
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	15
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2007.01.001
State	Published - Mar 1 2007

Funding

We are grateful to the National Institutes of Health (GM 49725 to R.B.S., and GM52419 and HL30050 to Prof. Bettie Sue Masters, in whose laboratory P.M. and L.J.R. work) for financial support of this work.

Keywords

Aminopiperidines
Aminopyrrolidines
Enzyme inhibitors
Neuronal nitric oxide synthase
Selective inhibition

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2007.01.001

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title = "Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors",

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-(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.",

keywords = "Aminopiperidines, Aminopyrrolidines, Enzyme inhibitors, Neuronal nitric oxide synthase, Selective inhibition",

author = "Jiwon Seo and Pavel Mart{\'a}sek and Roman, {Linda J.} and Silverman, {Richard B.}",

note = "Funding Information: We are grateful to the National Institutes of Health (GM 49725 to R.B.S., and GM52419 and HL30050 to Prof. Bettie Sue Masters, in whose laboratory P.M. and L.J.R. work) for financial support of this work. ",

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AU - Martásek, Pavel

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AU - Silverman, Richard B.

N1 - Funding Information: We are grateful to the National Institutes of Health (GM 49725 to R.B.S., and GM52419 and HL30050 to Prof. Bettie Sue Masters, in whose laboratory P.M. and L.J.R. work) for financial support of this work.

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N2 - 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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Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Abstract

Funding

Keywords

ASJC Scopus subject areas

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