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Skin and Musculoskeletal Diseases

Infectious Diseases

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Disease Domain	Count

Infectious Diseases	1

Top 5 Drug Type	Count

Small molecule drug	1

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Pfbc1(P. falciparum cytochrome bc1 complex)	1

Author: Chatelain, Eric ; Zuccotto, Fabio ; Deakyne, Julianna ; Breese, Karen J ; Feijens, Pim-Bart ; Maes, Louis ; Brunori, Gino ; White, Karen L ; Hendrickx, Sarah ; Van Pelt, Natascha ; González, Silvia ; Katneni, Kasiram ; Heppell, Jacob ; Islam, Rafiqul ; Chemi, Giulia ; Shackleford, David M ; Zulfiqar, Bilal ; Wall, Richard J ; Castañeda-Casado, Pablo ; Lyon, Jonathan J ; Wyllie, Susan ; Camino, Isabel ; Patil, Rahul ; Crighton, Elly ; Caljon, Guy ; Matheeussen, An ; Avery, Vicky M ; Braillard, Stéphanie ; Charman, Susan A ; Standing, David ; Yardley, Vanessa ; Chen, Gong ; Lee, Given ; Martinez Martinez, Maria S ; Marco, Maria ; Carvalho, Sandra ; Keenan, Martine ; Abbott, Michael

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 bc 1 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 bc 1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

01 Dec 2020·European Journal of Medicinal ChemistryQ1 · MEDICINE

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Q1 · MEDICINE

Article

Author: Riley, Jennifer ; Thompson, Andrew M ; Cornwall, Scott ; Keenan, Martine ; Read, Kevin D ; Avery, Vicky M ; O'Connor, Patrick D ; Francisco, Amanda F ; Sykes, Melissa L ; Chatelain, Eric ; Denny, William A ; Thompson, R C Andrew ; Charman, Susan A ; Perez, Catherine J ; Marshall, Andrew J ; White, Karen L ; Zulfiqar, Bilal ; Kelly, John M

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class.

13 Feb 2017·ChemistrySelect

Synthesis, Stereochemistry and Antiparasitic Activity of Derivatives of (4R)-4,6-Dihydroxy-N-methyl-1,2,3,4-tetrahydroisoquinoline

Author: Rattanajak, Roonglawan ; Cullen, Danica R. ; Chaplin, Jason ; Massera, Chiara ; Rohl, Andrew L. ; Mocerino, Mauro ; Kamchonwongpaisan, Sumalee ; Pengon, Jutharat

Condensation of phenylephrine with different aldehydes, under Pictet-Spengler cyclization conditions, afforded a series of tetrahydroisoquinoline derivatives, e.g., I as mixtures of cis/trans isomers.Single crystal X-ray anal. of the dibenzoate derivative of one of the 4-nitrophenyl isomers confirmed it to be the trans isomer.The conformation of the cis isomer was determined through computational experiments and comparison of the predicted and observed ¹H NMR spectra, particularly the magnitude of the coupling constantsFourteen tetrahydroisoquinoline derivatives were then evaluated for their activity towards T. b. rhodesiense, two strains of P. falciparum, and mammalian cells.The most promising derivative, the undecyl derivative, showed good activity towards T. b. rhodesiense with an IC₅₀ value in the sub-micromolar range and good selectivity over mammalian cells.The same derivative also showed activity against both strains of P. falciparum with IC₅₀ values in the low micromolar range.

100 Deals associated with Epichem Pty Ltd.

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100 Translational Medicine associated with Epichem Pty Ltd.

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Pipeline

Pipeline Snapshot as of 26 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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