DNDI-0690(DNDI-0690) - 在研适应症：利什曼病，内脏利什曼病_专利_临床

概要

基本信息

药物类型

小分子化药

别名-

靶点-

作用机制-

治疗领域

感染皮肤和肌肉骨骼疾病其他疾病

在研适应症

利什曼病内脏利什曼病

非在研适应症

皮肤利什曼病

原研机构

Global Alliance for TB Drug Development

在研机构

Drugs for Neglected Diseases initiative

Global Alliance for TB Drug Development

非在研机构-

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C18H15FN4O4

InChIKeyUSIKCXQLXHGVDD-OAHLLOKOSA-N

CAS号2097881-13-3

关联

2

项与 DNDI-0690 相关的临床试验

ISRCTN30122193 / Completed临床1期IIT

A Phase I, double-blind, randomised, single-centre, parallel-group, multiple-dose, dose-escalation, placebo-controlled study of the safety, tolerability and pharmacokinetics of DNDI-0690 after oral dosing in healthy subjects

开始日期2020-12-20

申办/合作机构

Drugs for Neglected Diseases initiative

NCT03929016 / Completed临床1期IIT

A Phase I, Double-blind, Randomised, Single Centre, Parallel Group, Single-dose, Dose-escalation, Placebo Controlled Study of the Safety, Tolerability and Pharmacokinetics of DNDI-0690 After Oral Dosing in Healthy Subjects

This study will evaluate how the test medicine DNDI-0690 is taken up and broken down by the body and will also look at the safety and tolerability of the test medicine after a single dose. This is the first time the test medicine DNDI-0690 will be administered to humans.

开始日期2019-04-04

申办/合作机构

Drugs for Neglected Diseases initiative

100 项与 DNDI-0690 相关的临床结果

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100 项与 DNDI-0690 相关的转化医学

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100 项与 DNDI-0690 相关的专利（医药）

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6

项与 DNDI-0690 相关的文献（医药）

2023-04-01·Biomolecules

Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates.

Review

作者: Martínez-Valladares, María ; Murugesan, Sankaranarayanan ; García-Estrada, Carlos ; Balaña-Fouce, Rafael ; Reguera, Rosa M ; Pérez-Pertejo, Yolanda ; Holanda, Vanderlan Nogueira ; Domínguez-Asenjo, Bárbara

Due to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases.

2021-02-11·ACS Medicinal Chemistry Letters3区 · 医学

Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility

3区 · 医学

Article

作者: Chatelain, Eric ; Ma, Zhenkun ; Braillard, Stephanie ; Yardley, Vanessa ; Thompson, Andrew M. ; Franzblau, Scott G. ; Wan, Baojie ; Denny, William A. ; Cooper, Christopher B. ; O’Connor, Patrick D. ; Maes, Louis ; Launay, Delphine

Antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated in vitro and in vivo but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that O-carbamate 66 offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).

2021-01-01·European Journal of Medicinal Chemistry1区 · 医学

Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal

1区 · 医学

Article

作者: Thompson, Andrew M ; Wan, Baojie ; Maes, Louis ; Franzblau, Scott G ; Ma, Zhenkun ; Chatelain, Eric ; O'Connor, Patrick D ; Gupta, Suman ; Launay, Delphine ; Denny, William A ; Cooper, Christopher B ; Marshall, Andrew J ; Yardley, Vanessa ; Braillard, Stephanie

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

100 项与 DNDI-0690 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
利什曼病	临床1期	瑞士	Drugs for Neglected Diseases initiative	2022-01-30
内脏利什曼病	临床1期	-	Global Alliance for TB Drug Development	-
皮肤利什曼病	药物发现	英国	Drugs for Neglected Diseases initiative	2019-04-04