Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors

Davey, David D.; Adler, Marc; Arnaiz, Damian O.; Eagen, Keith; Erickson, Shawn D.; Guilford, William H.; Kenrick, Margaret; Morrissey, Michael M.; Ohlmeyer, Mike; Pan, Gonghua; Paradkar, Vidyadhar M.; Parkinson, John F.; Polokoff, Mark A.; Saionz, Kurt W.; Santos, Cecile; Subramanyam, Babu; Vergona, Ronald; Wei, Robert G.; Whitlow, Marc; Ye, Bin; Zhao, Ziyu; Devlin, James J.; Phillips, Gary B.

doi:10.1021/jm061319i

Cited by 65 publications

(52 citation statements)

References 21 publications

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“…Substrate competitive inhibitors such as GW274150 can compete with arginine transport mechanisms (Baydoun et al, 2006), but long-term consequences of interference with arginine transport/metabolism are unclear. Inhibition of iNOS dimerization provided another avenue for imparting greater isoform selectivity (Davey et al, 2007). BBS-4, one of the first-generation dimerization inhibitors based on the 2-imidazol-1-ylpyrimidine chemical scaffold, is also a potent inhibitor CYP3A4, thus limiting its use as pharmacological probe.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in primary human bronchial epithelial cells, the cellular half-life for iNOS dimers was reported to be ϳ1.6 h, which contrasts with reported values of 28 h for eNOS and 20 h for nNOS (Kolodziejski et al, 2004). The feasibility of inhibition or destabilization of the iNOS dimerization process, a protein-protein interaction process, by small-molecule ligands has been successfully demonstrated (Davey et al, 2007;Symons et al, 2009). Rapid cellular turnover of the iNOS dimer suggests the possibility of achieving superior isoform selectivity by targeting the dimerization process.…”

Section: Introductionmentioning

confidence: 93%

“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org (Davey et al, 2007), a reference N-substituted imidazole-based iNOS dimerization inhibitor, were synthesized at Kalypsys per published methods (Davey et al, 2007). …”

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confidence: 99%

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Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Symons

Nguyen²,

Massari³

et al. 2010

J Pharmacol Exp Ther

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Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo [4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and murine iNOS and nNOS (IC 50 values 50-400 nM), with marked selectivity against endothelial nitric-oxide synthase (IC 50 Ͼ15,000 nM). It has ideal drug like-properties, including excellent rodent and primate pharmacokinetics coupled with a minimal offtarget activity profile. In mice, KLYP961 attenuated endotoxinevoked increases in plasma nitrates, a surrogate marker of iNOS activity in vivo, in a sustained manner (ED 50 1 mg/kg p.o.). KLYP961 attenuated pain behaviors in a mouse formalin model (ED 50 13 mg/kg p.o.), cold allodynia in the chronic constriction injury model (ED 50 25 mg/kg p.o.), or tactile allodynia in the spinal nerve ligation model (ED 50 30 mg/kg p.o.) with similar efficacy, but superior potency relative to gabapentin, pregabalin, or duloxetine. Unlike morphine, the antiallodynic activity of KLYP961 did not diminish upon repeated dosing. KLYP961 also attenuated carrageenin-induced edema and inflammatory hyperalgesia and writhing response elicited by phenylbenzoquinone with efficacy and potency similar to those of celecoxib. In contrast to gabapentin, KLYP961 did not impair motor coordination at doses as high as 1000 mg/kg p.o. KLYP961 also attenuated capsaicin-induced thermal allodynia in rhesus primates in a dose-related manner with a minimal effective dose (Յ10 mg/kg p.o.) and a greater potency than gabapentin. In summary, KLYP961 represents an ideal tool with which to probe the physiological role of NO derived from iNOS and nNOS in human pain and inflammatory states.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Symons

Nguyen²,

Massari³

et al. 2010

J Pharmacol Exp Ther

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“…In contrast, imidazolebased dimerization inhibitors such as BBS-4 display an opposite profile, being substantially more potent in cell-based assays (Blasko et al, 2002;Davey et al, 2007). As seen in Fig.…”

Section: Klyp956 Inhibits Inos and Nnos In Cells But Not Inmentioning

confidence: 96%

KLYP956 Is a Non-Imidazole-Based Orally Active Inhibitor of Nitric-Oxide Synthase Dimerization

Symons¹,

Massari²,

Nguyen³

et al. 2009

Mol Pharmacol

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Nitric-oxide synthases (NOS) generate nitric oxide (NO) through the oxidation of L-arginine. Inappropriate or excessive production of NO by NOS is associated with the pathophysiology of various disease states. Efforts to treat these disorders by developing arginine mimetic, substrate-competitive NOS inhibitors as drugs have met with little success. Small-moleculemediated inhibition of NOS dimerization represents an intriguing alternative to substrate-competitive inhibition. An ultra-high-throughput cell-based screen of 880,000 small molecules identified a novel quinolinone with inducible NOS (iNOS) inhibitory activity. Exploratory chemistry based on this initial screening hit resulted in the synthesis of KLYP956, which inhibits iNOS at low nanomolar concentrations. The iNOS inhibitory potency of KLYP956 is insensitive to changes in concentrations of the substrate arginine, or the cofactor tetrahydrobiopterin. Mechanistic analysis suggests that KLYP956 binds the oxygenase domain in the vicinity of the active site heme and inhibits iNOS and neuronal NOS (nNOS) by preventing the formation of enzymatically active dimers. Oral administration of KLYP956 [N-(3-chlorophenyl)-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide] inhibits iNOS activity in a murine model of endotoxemia and blocks pain behaviors in a formalin model of nociception. KLYP956 thus represents the first nonimidazole-based inhibitor of iNOS and nNOS dimerization and provides a novel pharmaceutical alternative to previously described substrate competitive inhibitors.The overproduction of nitric oxide (NO) has been implicated in the pathophysiology of a broad range of human diseases including pain, inflammation, migraine and neurodegenerative disorders. Three nitric-oxide synthase (NOS) isoforms have been described, including endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). Data support the notion that the inhibition of iNOS and nNOS may have therapeutic utility in the treatment of a variety of disease states, including inflammation and pain. However, inhibition of eNOS is considered detrimental because it results in elevated systemic blood pressure. Among the three isoforms, iNOS generates stoichiometrically higher amounts of NO and is expressed at sites of inflammation. Irrespective of the source, excessive NO can generate peroxynitrite and other reactive species that can trigger protein nitrosylation, leading to tissue damage (Vallance and Leiper, 2002).NOS isoforms catalyze the NADPH-and O 2 -dependent oxidation of L-arginine to NO and citrulline, with N-hydroxy-L-arginine formed as an intermediate. NOS isoforms are flavoheme enzymes that are only active as homodimers. Each monomer has a carboxyl-terminal diflavin-reductase domain Article, publication date, and citation information can be found at

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“…Nitric oxide is a cytotoxic and cytostatic agent associated with phagocytic cells in the immune system [5][6][7]. The main focus of recent efforts toward the development of new i-NOS inhibitors concentrates on structure-based ligand design [8][9][10][11][12]. Quantitative structure activity relationships (QSAR) are the important applications of chemometrics giving useful information for the design of new molecules acting on a specific target [13].…”

Section: Introductionmentioning

confidence: 99%

Investigation on Quantitative Structure Activity Relationships of a Series of Inducible Nitric Oxide

Sharma

2016

Interdiscip Sci Comput Life Sci

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A series of 2-dihydro-4-quinazolin with potent highly selective inhibitors of inducible nitric oxide synthase activities was subjected to quantitative structure activity relationships (QSAR) analysis. Statistically significant equations with high correlation coefficient (r = 0.8219) were developed. The k-nearest neighbor model has showed good cross-validated correlation coefficient and external validation values of 0.7866 and 0.7133, respectively. The selected electrostatic field descriptors the presence of blue ball around R1 and R4 in the quinazolinamine moiety showed electronegative groups favorable for nitric oxide synthase activity. The QSAR models may lead to the structural requirements of inducible nitric oxide compounds and help in the design of new compounds.

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Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors

Cited by 65 publications

References 21 publications

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

KLYP956 Is a Non-Imidazole-Based Orally Active Inhibitor of Nitric-Oxide Synthase Dimerization

Investigation on Quantitative Structure Activity Relationships of a Series of Inducible Nitric Oxide

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