Open AccessDiscovery 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
Author(s) -
Benjamin R. Taft,
Fumiaki Yokokawa,
Tom Kirrane,
Anne-Catherine Mata,
Richard S.P. Huang,
Nicole Blaquière,
Grace Waldron,
Bin Zou,
Oliver Simon,
Subramanyam Vankadara,
Wai Ling Chan,
Mei Ding,
Sandra Phek Lin 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,
H. D. Schulz,
Jessie Lim,
Siti Nurdiana Abas,
Xiaoman Ang,
Yugang Liu,
Íñigo Angulo-Barturen,
Marı́a Belén Jiménez-Dı́az,
Francisco Javier Gamo,
Benigno Crespo-Fernández,
Philip J. Rosenthal,
Roland A. Cooper,
Patrick K Tumwebaze,
Anna Caroline Campos Aguiar,
Brice Campo,
Simon F. Campbell,
Jürgen Wagner,
Thierry T. Diagana,
Christopher R. Sarko
Publication year - 2022
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01995
Subject(s) - pharmacology , plasmodium falciparum , artemisinin , potency , dosing , chemistry , pharmacokinetics , drug , malaria , toxicity , ec50 , in vitro , medicine , immunology , biochemistry , organic chemistry
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.