A series of 5-aryl-2-amino-imidazothiadiazole (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 (EC50 = 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 (T1/2) 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.
By Benjamin R. Taft, Fumiaki Yokokawa, Tom Kirrane, Anne-Catherine Mata, Richard Huang, Nicole Blaquiere, Grace Waldron, Bin Zou, Oliver Simon, Subramanyam Vankadara, Wai Ling Chan, Mei Ding, Sandra Sim, Judith Straimer, Armand Guiguemde, Suresh B. Lakshminarayana, Jay Prakash Jain, Christophe Bodenreider, Christopher Thompson, Christian Lanshoeft, Wei Shu, Eric Fang, Jafri Qumber, Katherine Chan, Luying Pei, Yen-Liang Chen, Hanna Schulz, Jessie Lim, Siti Nurdiana Abas, Xiaoman Ang, Yugang Liu, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Francisco Javier Gamo, Benigno Crespo-Fernandez, Philip J. Rosenthal, Roland A. Cooper, Patrick Tumwebaze, Anna Caroline Campos Aguiar, Brice Campo, Simon Campbell, Jürgen Wagner, Thierry T. Diagana, and Christopher Sarko