scyx-7158 and Disease-Models--Animal

Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent

Topics: Animals; Antiprotozoal Agents; Benzoxazoles; Boron Compounds; Cricetinae; Disease Models, Animal; Dogs; Humans; Leishmaniasis, Visceral; Mice; Pyridines; Structure-Activity Relationship

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