Delving into the Latest Updates on VP-343 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

VP-343

Target

AVPR2

Action

antagonists

Mechanism

AVPR2 antagonists(Vasopressin V2 receptor antagonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Edema

Originator Organization

Wakamoto Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Wakamoto Pharmaceutical Co., Ltd.

License Organization-

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC32H29N3O3

InChIKeyUACMTQPSUBFZOR-FTJBHMTQSA-N

CAS Registry214143-14-3

Antileishmanial chemotherapy is currently limited due to severe toxic side effects and drug resistance. Hence, new antileishmanial compounds based on alternative approaches, mainly to avoid the emergence of drug resistance, are needed. The present work aims to decipher the mechanism of action of an antileishmanial drug candidate, named VP343, inhibiting intracellular Leishmania infantum survival via the host cell. Cell imaging showed that VP343 interferes with the fusion of parasitophorous vacuoles and host cell late endosomes and lysosomes, leading to lysosomal cholesterol accumulation and ROS overproduction within host cells. Proteomic analyses showed that VP343 perturbs host cell vesicular trafficking as well as cholesterol synthesis/transport pathways. Furthermore, a knockdown of two selected targets involved in vesicle-mediated transport, Pik3c3 and Sirt2, resulted in similar antileishmanial activity to VP343 treatment. This work revealed potential host cell pathways and targets altered by VP343 that would be of interest for further development of host-directed antileishmanial drugs.

15 Sep 2021·JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY

An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis

Article

Author: Cintrat, Jean-Christophe ; Pruvost, Alain ; Pons, Valérie ; Gillet, Daniel ; Vacus, Joël ; Cojean, Sandrine ; Barbier, Julien ; Nguyen, Laetitia ; Pomel, Sébastien ; Loiseau, Philippe M

Abstract:

Background:

This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania.

Objectives:

To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages.

Methods:

In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development.

Results:

VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline.

Conclusions:

VP343 has the properties of a good drug candidate and merits further investigations.

01 Mar 2007·Current pharmaceutical designQ4 · MEDICINE

Aquaretic Agents: Whats Beyond the Treatment of Hyponatremia?

Q4 · MEDICINE

Review

Author: Campo, Susanna ; Buemi, Michele ; Criseo, Manila ; Coppolino, Giuseppe ; Bolignano, Davide ; Romeo, Adolfo

Unlike the more commonly used diuretics, aquaretic agents can induce an increase in urinary volume without incurring a loss of electrolytes. These molecules belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate optional renal water re-absorption via the synthesis and expression of aquaporin-2. In view of their properties, they have become the agent of choice in the treatment of hyponatremic states with water retention, and different studies have demonstrated that they are more effective and practical to use than other traditional approaches in the treatment of diseases such as cirrhosis-related ascites, SIADH and, above all, heart failure. However, the future probably holds the promise of new and unexpected applications for this type of drug in the treatment of several conditions, including polycystic kidney and glomerular disease, glaucoma and Meniere's syndrome.

100 Deals associated with VP-343

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