Authors

Benjamin R. Taft, Novartis Institutes for Biomedical Research
Fumiaki Yokokawa, Novartis Institutes for Biomedical Research
Tom Kirrane, Novartis Institutes for Biomedical Research
Anne-Catherine Mata, Novartis Institutes for Biomedical Research
Richard Huang, Novartis Institutes for Biomedical Research
Nicole Blaquiere, Novartis Institutes for Biomedical Research
Grace Waldron, Novartis Institutes for Biomedical Research
Bin Zou, Novartis Institute for Tropical Diseases
Oliver Simon, Novartis Institute for Tropical Diseases
Subramanyam Vankadara, Novartis Institute for Tropical Diseases
Wai Ling Chan, Novartis Institute for Tropical Diseases
Mei Ding, Novartis Institute for Tropical Diseases
Sandra Sim, Novartis Institute for Tropical Diseases
Judith Straimer, Novartis Institute for Tropical Diseases
Armand Guiguemde, Novartis Institute for Tropical Diseases
Suresh B Lakshminarayana, Novartis Institute for Tropical Diseases
Jay Prakash Jain, Novartis Institute for Tropical Diseases
Christopher Bodenreider, Novartis Institute for Tropical Diseases
Christopher Thompson, Novartis Institutes for Biomedical Research
Christian Lanshoeft, Novartis Institutes for Biomedical Research
Wei Shu, Novartis Institutes for Biomedical Research
Eric Fang, Novartis Institutes for Biomedical Research
Jafri Qumber, Novartis Institute for Tropical Diseases
Katherine Chan, Novartis Institute for Tropical Diseases
Luying Pei, Novartis Institute for Tropical Diseases
Yen-Liang Chen, Novartis Institute for Tropical Diseases
Hanna Schulz, Novartis Institute for Tropical Diseases
Jessie Lim, Novartis Institute for Tropical Diseases
Siti Nurdiana Abas, Novartis Institute for Tropical Diseases
Xiaoman Ang, Novartis Institute for Tropical Diseases
Yugang Liu, Novartis Pharmaceuticals Corporation
Iñigo Angulo-Barturen, The Art of Discovery
María Belén Jiménez-Díaz, The Art of Discovery
GlaxoSmithKline Gamo, GlaxoSmithKline
Benigno Crespo-Fernandez, GlaxoSmithKline
Philip J. Rosenthal, University of CaliforniaFollow
Roland A. Cooper, Dominican University of CaliforniaFollow
Patrick Tumwebaze, Infectious Diseases Research CollaborationFollow
Anna Caroline Campos Aguiar, University of São Paulo
Brice Campo, Medicines for Malaria Venture
Simon Campbell, Medicines for Malaria Venture
Jürgen Wagner, Novartis Institute for Tropical Diseases
Thierry T Diagana, Novartis Institute for Tropical Diseases
Christopher Sarko, Novartis Institutes for Biomedical Research

Department

Natural Sciences and Mathematics

Document Type

Article

Source

Journal of Medicinal Chemistry

Publication Date

3-10-2022

ISSN

1520-4804

Volume

65

Issue

5

First Page

3798

Last Page

3813

Abstract

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.

PubMed ID

35229610

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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