Delving into the Latest Updates on FFSC-1 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

eNOS/iNOS inhibitor (Dharma Biomedical), FFSC-1

Target

NOS2 x eNOS

Mechanism

NOS2 inhibitors(Nitric oxide synthase, inducible inhibitors), eNOS inhibitors(Nitric-oxide synthase, endothelial inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

InflammationMigraine Disorders

Originator Organization

Dharma Biomedical

Active Organization-

Inactive Organization

Dharma Biomedical

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

One hundred and forty-seven patients with MASH were recruited, and all tests were undertaken within 1 week of recruitment. With fibrotic MASH (NAS ≥ 4 and fibrosis stage ≥ 2) as the main outcome indicator, the diagnostic efficacy of eNO in identifying fibrotic MASH was compared to other validated models for advanced fibrosis requiring venesection, namely FAST, Agile 3⁺, and FIB-4 scores.

RESULTS:

The mean age was 40.36 ± 12.28 years, 73.5% were men. Mean body mass index was 28.83 ± 4.31 kg/m². The proportion of fibrotic MASH was 29.25%. The area under the receiver operating curve for eNO in diagnosing fibrotic MASH was 0.737 [95% CI 0.650-0.823], which was comparable to FAST (0.751 [0.656-0.846]), Agile 3⁺ (0.764 [0.670-0.858]), and FIB-4 (0.721 [0.620-0.821]) (all DeLong test p > 0.05). A cut-off of eNO <8.5 ppb gave a sensitivity of 86.0% and a negative predictive value of 88.5% for ruling-out fibrotic MASH. A cut-off of eNO >13.5 ppb provided a specificity of 91.3% and a positive predictive value of 65.4% for ruling-in fibrotic MASH. Sensitivity analyses demonstrated that the diagnostic efficacy of eNO was similar across characteristics such as age. Moreover, adding vibration-controlled transient elastography-LSM (liver stiffness measurement) reduced the uncertainty interval from 46.9% to 39.5%.

CONCLUSIONS:

The eNO-BT is a promising simple test for non-invasively identifying fibrotic MASH, and its performance is further improved by adding LSM measurement.

01 Dec 2024·LIFE SCIENCES

Neudesin, a secretory protein, attenuates activation of lipopolysaccharide-stimulated macrophages by suppressing the Jak/Stat1/iNOS pathway

Article

Author: Nakayama, Yoshiaki ; Shimizu, Ryohei ; Konishi, Morichika ; Masuda, Yuki

AIMS:

Neudesin, a heme-binding protein previously identified for its neurotrophic activity, has been implicated in various physiological and pathological processes, including immune regulation. However, its role in inflammatory macrophages remains unclear. Herein, we investigated the function of neudesin in the regulation of inflammatory macrophages.

MAIN METHODS:

In vitro experiments were performed in bone marrow-derived macrophages (BMDMs). In vivo experiments were conducted on neudesin knockout mice with a murine endotoxic shock model.

KEY FINDINGS:

We observed that neudesin deficiency led to elevated expression of Nos2/iNOS and increased nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BMDMs. Further, we found that neudesin, via the ERK/MAPK signaling pathway, promotes the proteasome-mediated degradation of Stat1, resulting in suppression of NO production. Furthermore, neudesin-deficient mice exhibited higher mortality rates following LPS administration, accompanied by increased Nos2/iNOS expression and nitrated proteins in the heart, compared to that in wildtype mice. Treatment with an iNOS inhibitor drastically improved the survival rate of neudesin-deficient mice, highlighting the significance of neudesin-mediated iNOS signaling in modulating immune responses and preventing excessive inflammation.

SIGNIFICANCE:

Our findings suggest that neudesin acts as an anti-inflammatory cytokine, suppressing NO production in inflammatory macrophages, underscoring its potential as a therapeutic target for immune-related disorders.

01 Dec 2024·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis, and biological evaluation of novel iNOS inhibitors as potent neuroprotective agents for ischemic stroke

Article

Author: Zhang, Yihua ; Wu, Jianbing ; Ye, Hui ; Kong, Tiantian ; Huang, Zhangjian ; Qu, Xiaohan ; Sun, Yuze ; Jin, Chengbin ; Chen, Huiqin ; Ji, Duorui ; Zhang, Libang ; Tao, Mingshu ; Li, Hongyu

Ischemic stroke (IS) is characterized by intricate pathophysiological mechanisms, where single-target treatments have often proven insufficient. Thus, multi-target therapeutic approaches are essential for effective IS management. In this study, we employed a molecular hybridization strategy, merging the structures of the iNOS inhibitor 1400W and the multi-target neuroprotective agent NBP, to develop a series of novel iNOS inhibitors BN-1 ∼ BN-4 with neuroprotective properties. Among these, BN-4 exhibited the most potent cell protective activity in OGD/R-induced SH-SY5Y and BV-2 cells. BN-4 not only reduced ROS levels induced by OGD/R in SH-SY5Y cells but also mitigated necrosis and apoptosis. By binding to iNOS in a manner similar to 1400W, BN-4 significantly inhibited iNOS activity. Furthermore, BN-4 demonstrated high stability, excellent blood-brain barrier permeability, and more than 100-fold increase in aqueous solubility compared to NBP. Additionally, BN-4 notably decreased infarct size and showed neuroprotective effects in tMCAO rats. These findings indicate that BN-4 holds promise as a novel candidate for treatment IS, offering enhanced therapeutic efficacy due to its superior pharmacokinetic and pharmacodynamic properties.

100 Deals associated with FFSC-1

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