2. Academic Validation
  3. 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

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

  • J Med Chem. 2022 Mar 10;65(5):3798-3813. doi: 10.1021/acs.jmedchem.1c01995.
Benjamin R Taft 1,  Fumiaki Yokokawa 1,  Tom Kirrane 1,  Anne-Catherine Mata 1,  Richard Huang 1,  Nicole Blaquiere 1,  Grace Waldron 1,  Bin Zou 2,  Oliver Simon 2,  Subramanyam Vankadara 2,  Wai Ling Chan 2,  Mei Ding 2,  Sandra Sim 2,  Judith Straimer 3,  Armand Guiguemde 3,  Suresh B Lakshminarayana 3,  Jay Prakash Jain 3,  Christophe Bodenreider 2,  Christopher Thompson 4,  Christian Lanshoeft 5,  Wei Shu 1,  Eric Fang 6,  Jafri Qumber 3,  Katherine Chan 3,  Luying Pei 3,  Yen-Liang Chen 3,  Hanna Schulz 3,  Jessie Lim 2,  Siti Nurdiana Abas 2,  Xiaoman Ang 2,  Yugang Liu 7,  Iñigo Angulo-Barturen 8,  María Belén Jiménez-Díaz 8,  Francisco Javier Gamo 9,  Benigno Crespo-Fernandez 9,  Philip J Rosenthal 10,  Roland A Cooper 11,  Patrick Tumwebaze 12,  Anna Caroline Campos Aguiar 13,  Brice Campo 14,  Simon Campbell 14,  Jürgen Wagner 2,  Thierry T Diagana 3,  Christopher Sarko 1
Affiliations

Affiliations

  • 1 Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 5959 Horton Street, Emeryville, California 94608, United States.
  • 2 Novartis Institute for Tropical Diseases, 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
  • 3 Novartis Institute for Tropical Diseases, 5959 Horton Street, Emeryville, California 94608, United States.
  • 4 Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
  • 5 Novartis Institutes for Biomedical Research, Fabrikstrasse 14, Basel CH-4056, Switzerland.
  • 6 Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, 5959 Horton Street, Emeryville, California 94608, United States.
  • 7 Technical Research and Development, Global Drug Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, New Jersey 07936, United States.
  • 8 The Art of Discovery, Astondo Bidea, BIC Bizkaia building, no. 612 Derio 48160 Bizkaia, Basque Country, Spain.
  • 9 Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid 28760, Spain.
  • 10 Department of Medicine, University of California, 533 Parnassus Avenue, San Francisco, California 94143, Unites States.
  • 11 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California 94901, United States.
  • 12 Infectious Diseases Research Collaboration, Plot 2C Nakasero Hill Road, P.O. Box 7475 Kampala, Uganda.
  • 13 São Carlos Institute of Physics, University of São Paulo, São Carlos, São Paulo 13563-120, Brazil.
  • 14 Medicines for Malaria Venture, 20 Route de Pre-Bois, 1215 Geneva 15, Switzerland.
PMID: 35229610 DOI: 10.1021/acs.jmedchem.1c01995
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 <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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145964
    98.84%, Antimalarial Agent