Leishmaniasis is one of 20 neglected tropical diseases (NTDs) designated by the World Health Organization. Caused by one of 20 protozoan species of the Leishmania genus, symptoms of the disease vary based on the causative species, with visceral leishmaniasis (VL) representing the most severe disease burden. The Drugs for Neglected Diseases initiative (DNDi) are pioneers in the advancement of safe and efficacious treatments for NTDs. The initial hit for this series was identified by DNDi, and while being cognizant of the target product profile developed by DNDi for VL, we have undertaken an optimization campaign. We will present our current multiparameter hit-to-lead optimization efforts around this series of diazaspirocyclic compounds identified as active against the two causative species of VL, L. donovani and L. infantum. Optimization of the in vitro SAR, thermodynamic aqueous solubility, lipophilicity and tier 1 absorption, distribution, metabolism and excretion properties will be discussed. In addition, we will describe efforts to modulate undesired hERG and CYP interactions that have been observed in this chemotype.

Multiparameter optimization of diazaspirocyclic compounds active against leishmaniasis

ACS Spring Meeting 2021

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