Delving into the Latest Updates on C-013 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Mechanism-

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

HeadacheTension-Type Headache

Originator Organization

1 A Pharma GmbH

Active Organization-

Inactive Organization

Curatis Pharma GmbH

1 A Pharma GmbH

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Candida auris (C. auris) has caused notable outbreaks across the globe in last decade and emerged as a life-threatening human pathogenic fungus. Despite significant advances in antifungal research, the drug resistance mechanisms in C. auris still remain elusive. Under such pressing circumstances, research on identification of new antifungal compounds is of immense interest. Thus, our studies aimed at identifying novel drug candidates and elucidate their biological targets in C. auris. After screening of several series of synthetic and hemisynthetic compounds from JUNIA chemical library, compounds C4 (butyl 2-(4-chlorophenyl)hydrazine-1-carboxylate) and C13 (phenyl 2-(4-chlorophenyl) hydrazine-1-carboxylate), belonging to the carbazate series, were identified to display considerable antifungal activities against C. auris as well as its fluconazole resistant isolates. Elucidation of biological targets revealed that C4 and C13 lead to changes in polysaccharide composition of the cell wall and disrupt vacuole homeostasis. Mechanistic insights further unravelled inhibited efflux pump activities of ATP binding cassette transporters and depleted ergosterol content. Additionally, C4 and C13 cause mitochondrial dysfunction and confer oxidative stress. Furthermore, both C4 and C13 impair biofilm formation in C. auris. The in vivo efficacy of C4 and C13 were demonstrated in Caenorhabditis elegans model after C. auris infection showing reduced mortality of the nematodes. Together, promising antifungal properties were observed for C4 and C13 against C. auris that warrant further investigations. To summarise, collected data pave the way for the design and development of future first-in-class antifungal drugs.

02 Oct 2024·Journal of Agricultural and Food Chemistry

Design, Synthesis, Antifungal Evaluation, and Three-Dimensional Quantitative Structure–Activity Relationship of Novel 5-Sulfonyl-1,3,4-thiadiazole Flavonoids

Article

Author: Dai, Peng ; Zhang, Weihua ; Ma, Zihua ; Li, Yufei ; Xia, Qing ; Jiao, Jian

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Rhizoctorzia solani (R. solani), Fusarium graminearum (F. graminearum), and Colletotrichum orbiculare (C. orbiculare). Specifically, the EC₅₀ values of 38 target compounds against R. solani were below 4 μg/mL, among which the compounds C13 (EC₅₀ = 0.49 μg/mL), C15 (EC₅₀ = 0.37 μg/mL), and C19 (EC₅₀ = 0.37 μg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC₅₀ = 0.52 μg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

01 Oct 2024·Journal of Neurology

Cenobamate: real-world data from a retrospective multicenter study

Article

Author: Schuh-Hofer, Sigrid ; Lauxmann, Stephan ; Alber, Michael ; Schreiber, Melanie ; Schriewer, Elisabeth ; Wolking, Stefan ; Weber, Yvonne ; Heuer, David ; Heckelmann, Jan ; Widman, Guido ; Fischer, Florian P ; Lerche, Holger

AbstractBackgroundClinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.MethodsWe conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.Results116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.ConclusionsCNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.

100 Deals associated with C-013

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