2. Academic Validation
  3. Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362

Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362

  • J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336.
Martin A Lowe 1,  Alvaro Cardenas 2,  Jean-Pierre Valentin 2,  Zhaoning Zhu 1,  Jan Abendroth 3,  Jose L Castro 1,  Reiner Class 2,  Annie Delaunois 2,  Renaud Fleurance 2,  Helga Gerets 2,  Vitalina Gryshkova 2,  Lloyd King 1,  Donald D Lorimer 3,  Malcolm MacCoss 4,  Julian H Rowley 1,  Marie-Luce Rosseels 2,  Leandro Royer 2,  Richard D Taylor 1,  Melanie Wong 1,  Oliver Zaccheo 1,  Vishal P Chavan 5,  Gokul A Ghule 5,  Bapusaheb K Tapkir 5,  Jeremy N Burrows 6,  Maëlle Duffey 6,  Matthias Rottmann 7 8,  Sergio Wittlin 7 8,  Iñigo Angulo-Barturen 9,  María Belén Jiménez-Díaz 9,  Josefine Striepen 10,  Kate J Fairhurst 10,  Tomas Yeo 10,  David A Fidock 10 11,  Alan F Cowman 12,  Paola Favuzza 12,  Benigno Crespo-Fernandez 13,  Francisco Javier Gamo 13,  Daniel E Goldberg 14,  Dominique Soldati-Favre 15,  Benoît Laleu 6,  Teresa de Haro 2
Affiliations

Affiliations

  • 1 UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom.
  • 2 UCB, Chem. du Foriest 1, 1420 Braine-l'Alleud, Belgium.
  • 3 UCB, 7869 NE Day Road West, Bainbridge Island, Washington 98110, United States.
  • 4 Bohicket Pharma Consulting LLC, 2556 Seabrook Island Road, Seabrook Island, South Carolina 29455, United States.
  • 5 Sai Life Sciences Limited, Plot DS-7, IKP Knowledge Park, Genome Valley, Turkapally, Hyderabad 500078, Telangana, India.
  • 6 Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland.
  • 7 Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123 Allschwil, Switzerland.
  • 8 University of Basel, 4002 Basel, Switzerland.
  • 9 The Art of Discovery, SL Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia Building, no. 612, Derio 48160, Bizkaia, Basque Country, Spain.
  • 10 Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 11 Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 12 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • 13 Global Health, GlaxoSmithKline R&D, Tres Cantos, 28760 Madrid, Spain.
  • 14 Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8051, St. Louis, Missouri 63110, United States.
  • 15 Department of Microbiology and Molecular Medicine, Faculty of Medicine, CMU, 1 rue Michel-Servet, CH-1211 Genève 4, Switzerland.
PMID: 36216349 DOI: 10.1021/acs.jmedchem.2c01336
Abstract

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria Parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

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