scyx-7158 and Trypanosomiasis--African

Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in 1 (NEU-1953), which was part of a series typically associated with poor aqueous solubility. In this report, we present various medicinal chemistry strategies that were used to increase the aqueous solubility and improve the physicochemical profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC

Topics: Animals; Blood Proteins; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Half-Life; Hepatocytes; Humans; Lapatinib; Mice; Microsomes, Liver; Quinazolines; Rats; Solubility; Structure-Activity Relationship; Thermodynamics; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African; Water

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Molecular Structure; Nitroimidazoles; Small Molecule Libraries; Structure-Activity Relationship; Trypanosomiasis, African

Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle.

Topics: Animals; Cell Cycle; Cell Line, Tumor; Cell Survival; Coloring Agents; Drug Design; Drug Discovery; ErbB Receptors; Humans; Indicators and Reagents; Lapatinib; Morpholines; Neglected Diseases; Phosphotransferases; Quinazolines; Structure-Activity Relationship; Tetrazolium Salts; Thiazoles; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African