Abstract
Nitric oxide (NO) is an endogenic product from plants, bacteria, and animal cells that has many important effects in those organisms. It is produced by nitric oxide synthase (NOS), which is found in main three isoforms, namely endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). It has an important role in homeostasis in different physiological systems, such as micro- and macro-vascularization, inhibition of platelet aggregation, and neurotransmission regulation in the central nervous, gastrointestinal, respiratory, and genitourinary systems. However, its overproduction has been associated with diseases such as arthritis, asthma, cerebral ischemia, Parkinson’s disease, neurodegeneration, and seizures. For this reason, and due to better understanding of the molecular mechanisms by which NO provokes those diseases, the interest on the design of NOS inhibitors with therapeutic purposes has highly increased. Based on the foregoing considerations, the proposal of this chapter is to show an overview about the design strategies, mechanism of action at the molecular level, and the main advances toward the search for selective NOS inhibitors available in the literature.
Keywords
- nitric oxide synthase isoforms
- structure-based drug design
- enzymatic inhibition
- selectivity
- heterocyclic compounds
1. Introduction
Nitric oxide (NO) is a diatomic neutral molecule, produced by bacteria, plants, and animals. Having one unpaired electron, its effect in biological system is related to the stabilization of this electron. It acts as dissolved nonelectrolyte in the organisms, except for the lungs, where it is found in gaseous state [1–3].
NO has gain importance mainly in the 1990s, and from then on, it has been studied to obtain interesting pharmacological effects. A review by Serafim and collaborators describes the state of the art of this compound use in drug design [4].
The basal NO production has an important contribution to homeostasis in different physiological systems, such as micro- and macro-vascularization, inhibition of platelet aggregation, and neurotransmission regulation in central nervous, gastrointestinal, respiratory, and genitourinary systems. However, NO overproduction has been strongly associated with some diseases such as arthritis, asthma, cerebral ischemia, Parkinson’s disease, neurodegeneration, and seizures [5–9].
Nitric oxide synthase (NOS) is the enzyme responsible for NO biosynthesis, and there are three main kinds of NOS isoforms [endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS)]. They are tetramers, constituted of two NOS monomers associated with two calmodulin monomers (CaM), and contain relatively tightly bound cofactors, BH4, FAD, FMN, and iron protoporphyrin IX (heme group). Their chemical function is to catalyze the reaction of l-arginine, NADPH, and oxygen to synthesize free radical NO, l-citrulline, and NADP (Figure 1) [10].
The substrate l-arginine establishes H-bond networks inside the catalytic site of NOS isoforms with the heme group, mainly due to the guanidine group, which is crucial to bind tightly using a salt-bridge interaction with the conserved carboxylate of Glu597 in human nNOS, Glu377 for iNOS and Glu361 for eNOS. In addition, l-arginine establishes H-bonds with the amide carbonyl from Trp592, in nNOS; with Trp372, in iNOS; and with Trp356, in eNOS. Moreover, α-amino group of l-arginine interacts through H-bond with the heme propionate side chain, and the guanidine
Exacerbated induction of iNOS is associated with septic shock, inflammatory, and noninflammatory impairment processes in different tissues/organs, and, likewise, the nNOS is triggered in neurotoxicity, neurodegeneration process, and proliferation increase of some neoplastic cell lines. Depending on the clinical condition, decreasing NO levels is necessary, and excellent benefits might be achieved using NOS inhibitors. However, it is much important not to inhibit eNOS, because of its central role in smooth muscle relax, controlling vascular tone and blood pressure [12–14].
The first inhibitors designed (during the1980s and early 1990s) were based on l-arginine, the substrate of the enzyme, and this approach led to potent compounds but with poor selectivity level among the isoforms. In the late 1990s, the first crystal structure of iNOS and eNOS was unveiled, showing the high degree of similarity particularly in the active site of both isoforms. The nNOS crystal structure was reported in 2002, allowing the design of selective inhibitors [15, 16]. It is worth noting that changes in some amino acids of the isoforms lead to differences in electronic and steric effects on the binding site region, which can be interesting for designing selective inhibitors [11, 15]. The active collaboration between Richard Silverman and Thomas Poulos’ groups has significantly contributed to this field, and some of their papers are discussed in this chapter.
NOS isoforms were validated as target for new drugs soon after their X-ray crystallography was available. From then on the design of effective and selective inhibitors has been an important approach in modern drug discovery involving NO biochemical pathways related to many dysfunctions of the human organism [12, 17–19].
2. Experimental studies
2.1. Inducible nitric oxide synthase (iNOS) inhibitors
Garvey and collaborators (1994) were the first to report highly selective iNOS inhibitors. The compounds were isothiourea derivatives (Figure 3—
The selective iNOS inhibition by aminoguanidine (Figure 3—
In 2000, Hagmann and collaborators explored the structure-activity relationships of a series of substituted 2-aminopyridines. Compounds 4,6-dialkyl substituted (Figure 3—
On the other hand, the 1,2-dihydro-4-quinazolinamine compound
Structural-based approach using crystal structure and mutagenesis have identified specific induced-fit binding mode, which can generate some conformational changes toward a new specific cavity. Garcin and coworkers showed the
Other compounds, as acetamidine derivatives (Figure 5—
A protein called SPSB2 plays an important role in modulating the activity of iNOS through its proteasomal degradation in defense cells. Since this complex is blocked, the NO production from iNOS is prolonged, increasing the killing activity against pathogen microorganisms, making it an interesting anti-infective target [32]. Some cyclic peptidomimetic compounds were designed using this strategy, and the most potent compound
High-throughput screening (HTS) strategy has been used to identify new iNOS inhibitors hits such as the compound
Phenylpyrroles, pyrazoles, urea kynurenamines, ethynylcyanodienones, and amidine derivatives (Figure 6—
Natural products have been a rich source of new bioactive molecules. Some examples in the NOS inhibition are a sesquiterpenoid, isolated from
2.2. Neuronal nitric oxide synthase (nNOS) inhibitors
In the beginning of the 1990s, efforts to design selective nNOS inhibitor compounds were addressed, using the substrate l-arginine as the prototype molecule. Series of analogs was synthesized to evaluate which molecular change could interfere in the ligand activity and selectivity over other isoforms. The first selective compound over nNOS was l-nitroarginine (Figure 7), producing hypertension in animals due to the lack of selectivity over eNOS. In addition, many peptide analogs were synthesized trying to obtain more promising compounds. After the X-ray crystal complex elucidation, structure-activity relationship findings of several scaffolds have been explored to identify the molecular basis of improving the selectivity toward neuronal isoform [15, 19].
The non-arginine-based compound 7-nitroindazole (Figure 7—
Entrena and collaborators, by using kynurenamine scaffold (Figure 7—
Aminopyridine is an attractive pharmacophoric group to bind in different regions of nNOS through H-bond. Using this moiety, compound
Concerning 4,5-dihydro-1-
Other interesting structures such as 2-aminoquinolines are effective scaffold to be included in the structure of nNOS inhibitors. Crystallography studies showed that those compounds act as competitive arginine mimics. This scaffold makes important H-bonds with the active-site Glu residue, and the non-coordinating aryl rings are stabilized in a hydrophobic pocket in the extremity of the substrate access channel. Moreover, this structural class showed good pharmacokinetic properties (Figure 8—
Exploring the heme-coordinating potential of imidazole group, a series of 2,4-disubtituted pyrimidine compounds (Figure 8—
Studies using aminopyridine-based scaffold with pyridine linker (Figure 8—
Rational strategy for identifying new nNOS inhibitors using a combination of virtual screening approach based on 3D pharmacophore model and molecular docking was able to identify a hit compound structurally different from the available inhibitors (Figure 8—
2.2.1. Double-headed nNOS inhibitors
Double-headed compounds have been explored by researches with the aim of obtaining high affinity binding in nNOS. Attaching a double-headed aminopyridine moiety in a compound led to a very potent (
Other symmetric double-headed aminopyridine series without charge groups were designed to contain a tail on the central aromatic ring. The objective is to achieve an interaction in the electronegative region in the catalytic site, since only the neuronal isoform has Asp597 in this region. Derivative
Furthermore, double-headed inhibitors containing chiral linkers derived from natural amino acids were designed and synthesized. The best compound (Figure 10—
2-Amino-4-methylpyridine groups with a chiral linker derived from proline were designed as selective nNOS inhibitors. They showed to be interesting as they can interact in a unique orientation, what led to selectivity toward neuronal isoform. The aminopyridine groups interact with a Glu592 residue and the heme propionate in nNOS active site. In addition, the nitrogen from pyrrolidine linker is important to contribute to additional hydrogen bonds to the heme propionate, resulting in the most potent compound (
In addition, using chiral double-headed inhibitors, the α-amino-functionalized aminopyridine derivative
The non-chiral double-headed thiophene-2-carboximidamide compound (Figure 10—
2.3. Bacterial nitric oxide synthase (bNOS) inhibitors
Bacterial nitric oxide synthase (bNOS) is present in many Gram-positive microorganisms and has been described as part of their defense system against other species and the oxidative stress provoked by antibiotics through NO releasing. Therefore, bNOS inhibition can increase the antibiotic potential and be harmful to bacterial cell [66].
A screening showed that some known nNOS inhibitors can decrease significantly the percent survival of
Exploring the potential of bNOS as a drug target, high selectivity levels are necessary to its inhibitors. In this context, the design of compounds that target the active and pterin-binding site has been considered an important strategy (Figure 11—
In addition, with the goal to identify the differences among bNOS and other isoforms, crystallography studies were performed using different inhibitor chemotypes. Researchers observed that Tyr706 from nNOS is conserved in bNOS (Tyr 357) and both have the same rotameric behavior, which is very different, compared with eNOS. This molecular feature can be useful to design new selective bNOS over eNOS inhibitor. Since the pharmacokinetic properties are very different between bNOS and nNOS, selectivity over the latter is not a trouble. However, due to steric hindrance in the tail end of thiophenecarboximidamide analogs, this scaffold can bind differently to bNOS comparatively to nNOS [69].
3. Clinical studies
A nonselective compound l-NMMA (Figure 12), also known as tilarginine, was evaluated clinically in Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status (TRIUMPH) study in North America and Europe with planned enrollment of 658 patients at 130 centers. The period of study was between January 2005 and August 2006 (the study was terminated early). Using 1 mg/kg bolus and 5 h infusion did not decrease the mortality rates in patients with refractory cardiogenic shock complicating myocardial infarction despite an open infarct artery. Although the good results showed in phase II, it has failed in phase III [70, 71]. In another study l-NMMA resulted in no differences in mean arterial pressure (MAP) after 2 h compared with placebo group [72].
Evaluating another inhibitor, N(G)-nitro-l-arginine methyl ester (Figure 12—l-NAME), in the treatment of refractory cardiogenic shock, the death at 1 month was 27% in the l-NAME group versus 67% in the control group [73]. Additional studies have been performed to further examination, concluding that TRIUMPH strongly indicated that nonselective NOS inhibitors are not clinically interesting [74].
Recent phase I study in advanced solid tumors with the iNOS inhibitor
4. Conclusions
Many scaffolds have been found to inhibit nitric oxide synthases. Some of them were presented in this chapter as promising for important therapeutic activity. It must be emphasized that the research about nitric oxide synthase inhibitors has expressively advanced thanks to the X-ray crystallographic studies of this enzyme. This helps the structure-based design approach toward the search for selective inhibitors of this enzyme and the comprehension of their mechanism of action. Notwithstanding, efforts have been made for imparting them with a drug-like profile.
Acknowledgments
The authors thank CAPES, for RAM Serafim scholarship, and CNPq, for EI Ferreira fellowship.
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