Inhibitors of human nitric oxide synthase isoforms with the carbamidine moiety as a common structural element

Moore, William M.; Webber, R. Keith; Fok, Kam F.; Jerome, Gina M.; Kornmeier, Christine; Tjoeng, Foe S.; Currie, Mark G.

doi:10.1016/0968-0896(96)00148-4

Cited by 37 publications

(21 citation statements)

References 21 publications

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“…Aminoguanidine (21) and methylguanidine (22) are two of the first compounds from this class that showed some potency and selectivity [85]. Aminoguanidine is selective for nNOS over eNOS, but is even more selective for iNOS over eNOS (IC 50 values for the human isozymes are 358, 168, and 1680 µM for nNOS, iNOS, and eNOS, respectively).…”

Section: Simple Guanidine Analoguesmentioning

confidence: 99%

Selective Neuronal Nitric Oxide Synthase Inhibitors

Erdal¹,

Litzinger²,

Seo³

et al. 2005

CTMC

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This review includes the non-patent literature up to October 2004 that deals with selective neuronal nitric oxide synthase inhibitors (highest potency is for the neuronal isozyme). Some non-selective inhibitors or selective inducible nitric oxide synthase inhibitors are mentioned if they are related to compounds that are discussed; structures of these compounds generally are not given. In vitro inhibition constants are given either as IC(50) values or as K(i)values. An IC(50) value, the inhibitor concentration that produces 50% inhibition in the presence of a constant concentration of substrate, is obtained by extrapolation of several rate data points to 50% inhibition. K(i) values are derived from several types of plots that relate the concentration of inhibitor with enzyme velocity in the presence of a variety of substrate concentrations [1]. The K(i) value can be estimated from the IC(50) value [2]. Although the two inhibition constants are related, they are not the same; generally, the reported K(i) values tend to be lower than the IC(50) values. If specifics are desired about how the data were collected, then the reader will have to look in the literature cited. No attempt was made to be exhaustive in citing all references related to specific inhibitors; rather, examples of literature references are given for each inhibitor described.

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Section: Simple Guanidine Analoguesmentioning

confidence: 99%

Selective Neuronal Nitric Oxide Synthase Inhibitors

Erdal¹,

Litzinger²,

Seo³

et al. 2005

CTMC

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“…Initially L-NNA was recognized as a competitive inhibitor of all NOSes having high selectivity to eNOS and nNOS over iNOS [58]. A later study, however, indicated only minor selectivity to nNOS and eNOS [59]. Such a pattern of selectivity correlates with a different mechanism of L-NNA binding to individual isoforms.…”

Section: The Literature Reviewmentioning

confidence: 99%

“…It is a nonselective competitive inhibitor of NOSes showing low micromolar affinities (Table 1, [59]). However, it may act as a reaction-based inactivator as well (Table 1, [78]).…”

Section: The Literature Reviewmentioning

confidence: 99%

Arginine-Based Inhibitors of Nitric Oxide Synthase: Therapeutic Potential and Challenges

Víteček

Lojek

Valacchi

et al. 2012

Mediators of Inflammation

159

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In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects both in vitro and in vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted.

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“…The key structural element responsible for the inhibitory properties of TU on NOS is the thioureylene moiety as indicated by the lack of activity of uracil (11). However, thioureylene per se is insufficient to account for NOS inhibition, since thiourea is inactive (11,16,17). Thus, the thioureylene functionality must be assembled with other critical elements into a well defined structural scaffold to be converted into a potential pharmacophore targeted to nNOS.…”

Section: Resultsmentioning

confidence: 98%