A new class of selective and potent inhibitors of neuronal nitric oxide synthase

Lowe, John; Qian, Weimin; Volkmann, Robert A.; Heck, Steven D.; Nowakowski, Jolanta; Nelson, Robert B.; Nolan, Charles E.; Liston, Dane; Ward, Karen; Zorn, Stevin H.; Johnson, Celeste; Vanase, M.; Faraci, W S; Verdries, Kimberly A.; Baxter, James H.; Doran, Shawn D.; Sanders, Matthew J.; Ashton, Mike; Whittle, Peter J.; Stefaniak, Mark H.

doi:10.1016/s0960-894x(99)00432-1

Cited by 22 publications

(15 citation statements)

References 4 publications

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“…Lowe and colleagues at Pfizer 21 reported the structure of 3 , a potent nNOS inhibitor with very high affinity for dopamine and serotonin receptors. Removal of the exterior hydrophobic group diminished off-target binding, and when an exterior polar amine was attached to an interior hydrophobic group (such as in 4 and 5 ) higher potency and isoform selectivity resulted.…”

Section: Introductionmentioning

confidence: 99%

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

Cinelli

Pensa

et al. 2015

J. Med. Chem.

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Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions, and b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed this rearranged scaffold significantly reduces off-target binding.

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Section: Introductionmentioning

confidence: 99%

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

Cinelli

Pensa

et al. 2015

J. Med. Chem.

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“…Compound 45 had an IC 50 of 140 nM for human nNOS, but only modest selectivity over eNOS (6 fold). 153 Compound 46 has an IC 50 of 70 nM for human nNOS with 50- and 10-fold selectivity over eNOS and iNOS, respectively. The compound possessed a good pharmacokinetic profile and was well tolerated and effective in vivo.…”

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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“…This continually growing list includes: guanidines [48], isothioureas [49,50], amidines [51,52], thiazines [53], imidazoles [54], indazoles [55], benzoxazoles [56], pyridines [57], pteridines [58], and 2-iminohomopiperidinium salts [59]. This continually growing list includes: guanidines [48], isothioureas [49,50], amidines [51,52], thiazines [53], imidazoles [54], indazoles [55], benzoxazoles [56], pyridines [57], pteridines [58], and 2-iminohomopiperidinium salts [59].…”

Section: Conformationally Restricted Arginine Analogsmentioning

confidence: 99%

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

Mašič

2006

CMC

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Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the arginine moiety in numerous peptidomimetic compounds (thrombin inhibitors, factor Xa inhibitors, factor VIIa inhibitors, integrin receptor antagonists, nitric oxide synthase inhibitors), with the aim of obtaining better activity, selectivity and oral bioavailability.

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A new class of selective and potent inhibitors of neuronal nitric oxide synthase

Cited by 22 publications

References 4 publications

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase

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

Arginine Mimetic Structures in Biologically Active Antagonists and Inhibitors

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