Taft, Benjamin, Yokokawa, Fumiaki, Kirrane, Tom, Remond, Anne-Catherine, Sarko, Christopher, Blaquiere, Nicole, Huang, Richard, Straimer, Judith, Lakshminarayana, Suresh, Jain, Jay Prakash, Thompson, Christopher, Guiguemde, Armand, Lanshoeft, Christian, Shu, Wei, Fang, Eric, Pei, Amy, Chen, Yen-Liang, Diagana, Thierry, Schulz, Hanna, Campo, Brice, Liu, Yugang, Waldron, Grace, Jafri, Q. and Chan, Katherine (2022) 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 Cure in Uncomplicated Malaria. Journal of medicinal chemistry, 65 (5). pp. 3786-3813. ISSN 0022-2623

Abstract

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by phenotype based hit-to-lead discovery using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antimalarial potency, selectivity against human kinases, ADMET properties, and extended pharmacological profiles culmi-nated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 M) and achieves ‘artemisinin-like’ kill kinetics in vitro with a parasite clearance time of <24 hours. INE963 (1) has a single dose ED90 = 11.7 mg/kg in the Pf-humanized SCID-mouse model and is fully curative without recrudescence with a single dose of 30 mg/kg. INE963 (1) also demonstrates a high barrier to resistance in drug selection studies conducted with P. falciparum blood stage cultures in vitro. In pharmacokinetic studies, INE963 (1) has low clearance (CL) with high volume of distribu-tion (Vss) across mouse, rat, dog, and thus a long half-life (T1/2) is projected in humans. Taken together, these properties craft a great 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.

Item Type:	Article
Date Deposited:	17 Feb 2026 00:45
Last Modified:	17 Feb 2026 00:45
URI:	https://oak.novartis.com/id/eprint/45694