TY - JOUR
T1 - 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.
AU - Taft, Benjamin R.
AU - Yokokawa, Fumiaki
AU - Kirrane, Tom
AU - Mata, Anne-Catherine
AU - Huang, Richard
AU - Blaquiere, Nicole
AU - Waldron, Grace
AU - Zou, Bin
AU - Simon, Oliver
AU - Vankadara, Subramanyam
AU - Chan, Wai Ling
AU - Ding, Mei
AU - Sim, Sandra
AU - Straimer, Judith
AU - Guiguemde, Armand
AU - Lakshminarayana, Suresh B
AU - Jain, Jay Prakash
AU - Bodenreider, Christopher
AU - Thompson, Christopher
AU - Lanshoeft, Christian
AU - Shu, Wei
AU - Fang, Eric
AU - Qumber, Jafri
AU - Chan, Katherine
AU - Pei, Luying
AU - Chen, Yen-Liang
AU - Schulz, Hanna
AU - Lim, Jessie
AU - Abas, Siti Nurdiana
AU - Ang, Xiaoman
AU - Liu, Yugang
AU - Angulo-Barturen, Iñigo
AU - Jiménez-Díaz, María Belén
AU - Gamo, GlaxoSmithKline
AU - Crespo-Fernandez, Benigno
AU - Rosenthal, Philip J.
AU - Cooper, Roland A.
AU - Tumwebaze, Patrick
AU - Aguiar, Anna Caroline Campos
AU - Campo, Brice
AU - Campbell, Simon
AU - Wagner, Jürgen
AU - Diagana, Thierry T
AU - Sarko, Christopher
N1 - Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society
PY - 2022/3
Y1 - 2022/3
N2 - 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/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.
AB - 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/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.
KW - Animals
KW - Antimalarials
KW - Folic Acid Antagonists
KW - Malaria
KW - Falciparum
KW - Mice
KW - SCID
KW - Plasmodium falciparum
KW - Folic Acid Antagonists/therapeutic use
KW - Mice, SCID
KW - Malaria/drug therapy
KW - Antimalarials/pharmacology
KW - Malaria, Falciparum/drug therapy
UR - https://scholar.dominican.edu/natural-sciences-and-mathematics-faculty-scholarship/88
M3 - Article
C2 - 35229610
VL - 65
SP - 3798
EP - 3813
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -