Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria

Abstract

A series of 5-aryl-2-amino-<u>i</u>midazo<u>t</u>hia<u>d</u>iazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage <i>Plasmodium falciparum</i> (<i>Pf</i>) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of <b>INE963</b> (<b>1</b>), which demonstrates potent cellular activity against <i>Pf</i> 3D7 (EC₅₀ = 0.006 μM) and achieves "artemisinin-like" kill kinetics <i>in vitro</i> with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the <i>Pf</i>-humanized severe combined immunodeficient mouse model. <b>INE963</b> (<b>1</b>) also exhibits a high barrier to resistance in drug selection studies and a long half-life (<i>T</i>_1/2) across species. These properties suggest the significant potential for <b>INE963</b> (<b>1</b>) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, <b>INE963</b> (<b>1</b>) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.