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.

A series of 5-aryl-2-amino-midazohiaiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage () 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 (), which demonstrates potent cellular activity against 3D7 (EC = 0.006 μM) and achieves "artemisinin-like" kill kinetics with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the -humanized severe combined immunodeficient mouse model. () also exhibits a high barrier to resistance in drug selection studies and a long half-life () across species. These properties suggest the significant potential for () to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, () was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.