Pharmacological profile of FR260330, a novel orally active inducible nitric oxide synthase inhibitor

Chida, Noboru; Hirasawa, Yoshimi; Ohkawa, Takehiko; Ishii, Yoshinori; Sudo, Yuji; Tamura, Kouichi; Mutoh, Seitaro

doi:10.1016/j.ejphar.2004.12.028

Cited by 21 publications

(20 citation statements)

References 19 publications

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“…FK330 is a selective iNOS inhibitor believed to act by binding to the oxygenase domain of the inactive iNOS monomer, thereby preventing formation of the active iNOS dimer. Indeed, in our previous in vitro study, FK330 exhibited potent inhibitory activity against cytokine-induced iNOS activity in human colon cancer cells (DLD-1) (19). Collectively, these results suggest that excessive NO production may accelerate liver IRI and that inhibition of NO induced by iNOS is an important pharmacological effect of FK330.…”

Section: Discussionmentioning

confidence: 85%

“…, is a newly developed specific iNOS inhibitor with a novel mechanism of action that inhibits iNOS monomer dimerization and selectively blocks enzyme activity (19). Recently, the effective dose of FK330 to inhibit NO production, and its efficacy to prevent chronic aortic graft rejection in rats (20) and renal IRI in monkeys (21) have been shown.…”

Section: Fk330 (Fr260330)mentioning

confidence: 99%

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FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

Tsuchihashi

Kaldas

Chida

et al. 2006

American Journal of Transplantation

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Nitric oxide (NO), produced via inducible NO synthase (iNOS), is implicated in the pathophysiology of liver ischemia/reperfusion injury (IRI).We examined the effects of a novel iNOS inhibitor, FK330 (FR260330), in well-defined rat liver IRI models. In a model of liver cold ischemia followed by ex vivo reperfusion, treatment with FK330 improved portal venous flow, increased bile production and decreased hepatocellular damage. FK330 prevented IRI in rat model of 40-h cold ischemia followed by syngeneic orthotopic liver transplantation (OLT), as evidenced by: (1) increased OLT survival (from 20% to 80%); (2) decreased hepatocellular damage (serum glutamic oxaloacetic transaminase/glutamic pyruvic transaminase levels); (3) improved histological features of IRI; (4) reduced intrahepatic leukocyte infiltration, as evidenced by decreased expression of P-selectin/intracellular adhesion molecule 1, ED-1/CD3 cells and neutrophils; (5) depressed lymphocyte activation, as evidenced by expression of pro-inflammatory cytokine (TNF-a , IL-1b , IL-6) and chemokine (IP-10, MCP-1, MIP-2) programs; (6) prevented hepatic apoptosis and down-regulated Bax/Bcl-2 ratio. Thus, by modulating leukocyte trafficking and cell activation patterns, treatment of rats with FK330, a specific iNOS inhibitor, prevented liver IRI. These results provide the rationale for novel therapeutic approaches to maximize organ donor pool through the safer use of liver grafts despite prolonged periods of cold ischemia.

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Section: Discussionmentioning

confidence: 85%

Section: Fk330 (Fr260330)mentioning

confidence: 99%

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

Tsuchihashi

Kaldas

Chida

et al. 2006

American Journal of Transplantation

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“…In summary, the overall similarity between the NOS inhibitory profiles of BBS-4 and KLYP956 suggest that the latter acts via destabilization of iNOS and nNOS dimers, although details of the modes of action may differ between the two compounds. A peptide-based compound lacking an imidazole has been described to have iNOS dimer destabilizing properties, providing further evidence that an imidazole is not essential for this mechanism of inhibition (Chida et al, 2005).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Several groups have described small molecules capable of interfering with the formation and enzymatic activity of NOS dimers. With the exception of a peptide-derived compound (Chida et al, 2005), all iNOS dimerization inhibitors described to date contain an N-substituted imidazole moiety that is thought to directly coordinate the heme iron in the active site of the enzyme (Sennequier et al, 1999;McMillan et al, 2000;Ohtsuka et al, 2002;Sohn et al, 2008). Given that nonsubstrate mimetic inhibitors, such as those that act by blocking formation of the enzymatically active dimer, are likely to have distinct in vivo profiles, we conducted a cell-based high-throughput screen of approximately 880,000 small molecules to discover novel, nonarginine, non-imidazole-based inhibitors of recombinant human iNOS.…”

mentioning

confidence: 99%

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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“…Its molecular formula is C 29 H 28 CIF 3 N 6 O 4 S⅐2H 2 O, and its molecular weight is 653.05 (22). FR260330 inhibited NOx production both in rat and human cells, with a dosedependent outcome (IC 50 values ranged around 10 nM).…”

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confidence: 98%

Effect of a Novel Inducible Nitric Oxide Synthase Inhibitor, FR260330, in Prevention of Renal Ischemia/Reperfusion Injury in Vervet Monkeys

et al. 2006

Transplantation

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Cytotoxic nitric oxide (NO) is produced during ischemia/reperfusion (I/R) injury by the expression of inducible NO synthase (iNOS). Therefore, continuous iNOS inhibition might prevent early graft dysfunction. FR260330, a potent and selective inhibitor of iNOS activity, impedes the dimmerization of iNOS monomer. In this study, the effect of FR260330 in the prevention of renal I/R injury was evaluated in the model of one kidney ischemia in Vervet monkeys. A total of 18 male Vervet monkeys were randomly assigned to two equal groups (n=9). Transient (60 min) left renal ischemia was produced by simultaneous contralateral nephrectomy in treated (FR260330 20 mg/kg/day) and placebo control groups. Renal function and other biochemical parameters as well as FR260330 concentrations were studies until day 15 after I/R injury. All monkeys survived after 60 min I/R injury until sacrifice on day 15. Serum creatinine in the untreated controls increased significantly in comparison to the FR260330-treated group on days 2, 3, 4, and 7 (P<0.05). Plasma FR260330 concentration after oral administration showed that C(max) was 3.251+/-2.526 microg/ml, and T(max) was 4 hr. This study thus finds that FR260330, as a selective iNOS inhibitor, effectively prevents renal I/R injury in Vervet monkeys.

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Pharmacological profile of FR260330, a novel orally active inducible nitric oxide synthase inhibitor

Cited by 21 publications

References 19 publications

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

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

Effect of a Novel Inducible Nitric Oxide Synthase Inhibitor, FR260330, in Prevention of Renal Ischemia/Reperfusion Injury in Vervet Monkeys

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