Chapter 2 Advancements in the Development of Nitric Oxide Synthase Inhibitors

Maddaford, Shawn P.; Annedi, Subhash C.; Ramnauth, Jailall; Rakhit, Suman

doi:10.1016/s0065-7743(09)04402-9

Cited by 33 publications

(43 citation statements)

References 76 publications

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“…4 Although there is low homology among the three NOS primary sequences (~50%), the active sites of the enzymes appears to be relatively conserved with 16 out of 18 residues within 6 Å being identical, presumably explains the difficulty obtaining selective NOS The pharmacophore model we adopted for the arginine binding site of the NOS enzyme includes a guanidine isosteric group (amidine group) and a basic amine group, both attached to a central aryl scaffold (indole core) as shown in Figure 1. 4,15 The amidine group makes an important bidentate interaction with the conserved glutamic acid residue to achieve the necessary potency; whereas the basic amine is assumed to provide the nNOS isoform selectivity. 15 Our design strategy is based on an indole core as an aryl scaffold and exploring various basic amine side chains for achieving the NOS isoform selectivity.…”

Section: Introductionmentioning

confidence: 99%

“…3 Therefore, the development of selective NOS inhibitors is of considerable interest, both from a therapeutic perspective and also as specific pharmacological tools. 4 Although there is low homology among the three NOS primary sequences (~50%), the active sites of the enzymes appears to be relatively conserved with 16 out of 18 residues within 6 Å being identical, presumably explains the difficulty obtaining selective NOS inhibitors. 5 Investigation into the synthesis and chemistry of novel isoform-selective NOS inhibitors has been an ongoing challenge, even though the general pharmacophore requirements are well established.…”

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confidence: 99%

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1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Renton¹,

Speed²,

Maddaford³

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain. Keywords1,6-Disubstitued indole derivatives; Nitric oxide; Nitric oxide synthase; Nitric oxide synthase inhibitors; Selective neuronal nitric oxide synthase inhibitors Nitric oxide (NO) is an inorganic free radical that has diverse roles both in normal and pathological processes, including the regulation of blood pressure, neurotransmission and macrophage defense systems. 1 NO is synthesized from the enzyme catalysis of L-arginine to L-citrulline by three isoforms of nitric oxide synthase (NOS): two constitutive forms in neuronal cells (nNOS) and endothelial cells (eNOS), and an inducible form in macrophage cells (iNOS). Overstimulation or overproduction of NO by nNOS and iNOS has been shown to play a key role in several disorders, including septic shock, arthritis, diabetes, ischemiareperfusion injury, pain and various neurodegenerative diseases. 2 However, any inhibitors to treat these conditions must avoid eNOS inhibition as this will lead to unwanted effects such as enhanced white cell and platelet activation, hypertension and atherogenesis. 3 Therefore, the development of selective NOS inhibitors is of considerable interest, both from a therapeutic perspective and also as specific pharmacological tools. 4 Although there is low homology among the three NOS primary sequences (~50%), the active sites of the enzymes appears to be relatively conserved with 16 out of 18 residues within 6 Å being identical, presumably explains the difficulty obtaining selective NOS The pharmacophore model we adopted for the arginine binding site of the NOS enzyme includes a guanidine isosteric group (amidine group) and a basic amine group, both attached to a central aryl scaffold (indole core) as shown in Figure 1. 4,15 The amidine group makes an important bidentate interaction with the conserved glutamic acid residue to achieve the necessary potency; whereas the basic amine is assumed to provide the nNOS isoform selectivity. 15 Our design strategy is based on an indole core as an aryl scaffold and exploring various basic amine side chains for achieving the NOS isoform selectivity. As part of our ongoing efforts to find small molecule selective nNOS inhibitors for treating CNS disorders, herein we report the synthesis and biological activity evaluations of a series of 1,6-disubstituted indole derivatives and in vivo activity of (R)-8 in a rat model relevant to migraine pain. 15 Two general approaches were undertaken for the prepa...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Renton¹,

Speed²,

Maddaford³

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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“…9 Therefore, the development of selective nNOS inhibitors is of critical interest and derives both from a therapeutic perspective and from their use as specific pharmacological tools. 10 …”

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confidence: 99%

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

Jing¹,

Roman

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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To develop potent and selective nNOS inhibitors, a new series of double-headed molecules with chiral linkers that derive from natural amino acid derivatives have been designed and synthesized. The new structures integrate a thiophenecarboximidamide head with two types of chiral linkers, presenting easy synthesis and good inhibitory properties. Inhibitor (S)-9b exhibits a potency of 14.7 nM against nNOS and is 1134 and 322-fold more selective for nNOS over eNOS and iNOS, respectively. Crystal structures show that the additional binding between the aminomethyl moiety of 9b and propionate A on the heme and tetrahydrobiopterin (H4B) in nNOS, but not eNOS, contributes to its high selectivity. This work demonstrates the advantage of integrating known structures into structure optimization, and it should be possible to more readily develop compounds that incorporate bioavailability with these advanced features. Moreover, this integrative strategy is a general approach in new drug discovery.

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“…They are described in detail in other excellent, recent review articles. 134, 164, 165 The compounds described above have all been active site inhibitors. Inhibitors that disrupt dimerization 166 and inhibitors that displace tetrahydrobiopterin 167 also have been explored as NOS inhibitors.…”

Section: Neuronal Nitric Oxide Synthase Inhibitorsmentioning

confidence: 99%

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

et al. 2013

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The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms; N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

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Chapter 2 Advancements in the Development of Nitric Oxide Synthase Inhibitors

Cited by 33 publications

References 76 publications

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Combination of chiral linkers with thiophenecarboximidamide heads to improve the selectivity of inhibitors of neuronal nitric oxide synthase

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

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