9 research outputs found
DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.</p
DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.</p
DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis
Exploration of 6-methyl-7-(Hetero)Aryl-7-Deazapurine ribonucleosides as antileishmanial agents
Exploration of 6-methyl-7-(Hetero)Aryl-7-Deazapurine ribonucleosides as antileishmanial agents
Development of novel isoindolone-based compounds against Trypanosoma brucei rhodesiense
This study identified the isoindolone ring as a scaffold for novel agents against Trypanosoma brucei rhodesiense and explored the structureâactivity relationships of various aromatic ring substitutions. The compounds were evaluated in an integrated inâ
vitro screen. Eight compounds exhibited selective activity against T. b. rhodesiense (IC(50)<2.2â
ÎŒm) with no detectable side activity against T. cruzi and Leishmania infantum. Compound 20 showed low nanomolar potency against T. b. rhodesiense (IC(50)=40â
nm) and no toxicity against MRCâ5 and PMM cell lines and may be regarded as a new lead template for agents against T. b. rhodesiense. The isoindoloneâbased compounds have the potential to progress into lead optimization in view of their highly selective inâ
vitro potency, absence of cytotoxicity and acceptable metabolic stability. However, the solubility of the compounds represents a limiting factor that should be addressed to improve the physicochemical properties that are required to proceed further in the development of inâ
vivoâactive derivatives
PLGA nanoparticles and nanosuspensions with amphotericin B : potent **in vitro** and **in vivo** alternatives to Fungizone\uae and AmBisome\uae
Highly selective inhibitors of dipeptidyl peptidase 9 (DPP9) derived from the clinically used DPP4-inhibitor vildagliptin
Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity
Visceral leishmaniasis is a severe
parasitic disease that is one
of the most neglected tropical diseases. Treatment options are limited,
and there is an urgent need for new therapeutic agents. Following
an HTS campaign and hit optimization, a novel series of amino-pyrazole
ureas has been identified with potent in vitro antileishmanial activity.
Furthermore, compound <b>26</b> shows high levels of in vivo
efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series