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- i midazo t hia d iazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum ( Pf ) 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 INE963 ( 1 ), which demonstrates potent cellular activity against Pf 3D7 (EC 50 = 0.006 μM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf -humanized severe combined immunodeficient mouse model. INE963 ( 1 ) also exhibits a high barrier to resistance in drug selection studies and a long half-life ( T 1/2 ) across species. These properties suggest the significant potential for INE963 ( 1 ) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 ( 1 ) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.