Delving into the Latest Updates on FK-409 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

FK 409, FR 900409, FR 900411

+ [1]

Target-

Action

donors

Mechanism

Nitric oxide donors

Therapeutic Areas

Nervous System DiseasesCardiovascular DiseasesOther Diseases+ [2]

Active Indication-

Inactive Indication

Angina PectorisCardiac transplant rejectionHypertension+ [3]

Originator Organization

Astellas Pharma, Inc.

Active Organization-

Inactive Organization

Astellas Pharma, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC8H13N3O4

InChIKeyMZAGXDHQGXUDDX-MXRGZUMGSA-N

CAS Registry92454-60-9

Gastrointestinal dysmotility is frequently observed under septic conditions, yet its precise mechanisms remain to be elucidated. In this study, we have investigated the mechanisms of intestinal dysmotility by lipopolysaccharides (LPS) and the role of the interstitial cells of Cajal (ICCs) in motility disorders using a mouse endotoxin model. The injection of LPS caused time- and dose-dependent decreases in the intestinal contractility, which was associated with similar time- and dose-dependent decreases in the number of KIT-positive fibroblast-like cells located in the intermuscular layer. iNOS inhibitors, L-NAME and aminoguanidine (AG), but not 7-nitroindazole (7NI), a specific nNOS inhibitor, inhibited the LPS-induced decreases in both the contractility and the number of KIT-positive cells. A spontaneous NO releaser, FK409, not only diminished spontaneous electrical potential and phasic contractions, but also decreased the number of KIT-positive cells. Pretreatment with gadolinium inhibited the activation of macrophages and the induction of iNOS in intestinal resident macrophages, and restored the number of KIT-positive cells and intestinal contractions. These results suggested that NO produced from intestinal macrophages via iNOS induced by LPS, may be involved in the ICCs injury and intestinal dysmotility under septic conditions.

01 Jan 2012·Clinical hemorheology and microcirculationQ4 · MEDICINE

The NO-donor FK409 improves mechanical properties of activated neonatal PMN

Q4 · MEDICINE

Article

Author: Craciun, E. ; Koch, L. ; Fritzsching, B. ; Frommhold, D. ; Kuss, N. ; Pöschl, J. ; Ruef, P.

BACKGROUND:

Activated polymorphonuclear neutrophils (PMN) play an important role in the microcirculation. Nitric oxide (NO) reduces the sequestration of PMN in the narrow vessels of various organs and, therefore, may reduce organ injury during inflammation.

OBJECTIVES:

Since PMN of term neonates show various functional differences compared to PMN in adults (decreased chemotaxis, decreased intracellular killing, decreased adhesion), we studied the influence of the semi-synthetical NO-donor FK-409 (4-Ethyl-2-hydroxyimino-5-nitro-3-hexenamide) on the deformability of IL-8 activated PMN in term neonates and adults.

METHODS:

A cell transit analyzer (CTA) was used to study transit times of individual PMN through 8 μm filter pores, neutrophil elastase concentrations were determined by enzyme-immunoessay and activation of PMN was classified by mircroscopic evaluation.

RESULTS:

The transit times of PMN activated by IL-8 in adults were 9.3 ± 2.9 s, in term neonates 10.7 ± 3.3 s. FK-409 improved the transit time of activated PMN in adults (5.4 ± 1.6 s) and in term neonates (5.6 ± 1.1 s). Despite of the functional differences of PMN in term neonates and adults, the improvement of the transit times by FK-409 was not different between the two groups. The NO donor decreased the neutrophil elastase concentrations and the morphological signs of activation in neonates and adults.

CONCLUSIONS:

We conclude that the NO-donor FK-409 improves the microcirculation by increasing the deformability of IL-8 activated PMN. NO may reduce in neonates tissue damage by reduced PMN sequestration due to decreased PMN rigidity.

01 Dec 2008·Life sciencesQ3 · MEDICINE

Dual role of nitric oxide in gastric hypersecretion in the distended stomach: Inhibition of acid secretion and stimulation of pepsinongen secretion

Q3 · MEDICINE

Article

Author: Yoshikawa, Toshikazu ; Takeuchi, Koji ; Ito, Yasuyuki ; Mitsufuji, Shoji ; Okuda, Sayaka ; Ohkawa, Fumikazu ; Kato, Shinichi

AIMS:

We investigate the role of nitric oxide (NO) in the hypersecretion of acid and pepsinogen induced by stomach distension.

MAIN METHOD:

The rat stomach was distended by instillation of saline through an acute fistula under urethane anesthesia.

KEY FINDINGS:

Both secretions of acid and pepsinogen were increased by the distension depending on the volume of saline introduced, and responses were attenuated by bilateral cervical vagotomy or prior administration of atropine. N(G)-nitro-l-arginine methyl ester (L-NAME) had a dual effect on these responses, causing an increase in the acid response and a decrease in the pepsin response, both in an l-arginine-sensitive manner. Distension of the stomach increased the luminal NO release; this response was suppressed by vagotomy and L-NAME. Intragastric application of FK409, a NO donor, dose-dependently increased pepsinogen secretion while decreasing acid secretion in the stomach without distension. However, serosal application of both FK409 and 8-bromo-guanosine cyclic 3', 5'-monophosphate (8-Br-cGMP) stimulated the secretion of pepsinogen in isolated mouse stomachs in vitro. The stimulatory effect of FK409 on pepsinogen secretion was totally abolished by LY83583, a guanylate cyclase inhibitor.

SIGNIFICANCE:

Distension of the stomach increases both acid and pepsinogen secretion through a vagal-cholinergic pathway in addition to the luminal release of NO, and NO affects these responses in opposite ways, suppressing the acid response while enhancing the pepsin response, both mediated by a guanylate cyclase/cGMP pathway.

100 Deals associated with FK-409

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Angina Pectoris	Phase 2	Japan	-	-
Angina Pectoris	Phase 2	-	Astellas Pharma, Inc.	-
Hypertension	Phase 2	Japan	-	-
Hypertension	Phase 2	-	Astellas Pharma, Inc.	-
Cardiac transplant rejection	Preclinical	Japan	-	-
Lung transplant rejection	Preclinical	Japan	-	-
Peptic Ulcer	Preclinical	Japan	-	-
Thrombosis	Preclinical	Japan	-	-