2. Academic Validation
  3. Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model

Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model

  • J Biol Chem. 2010 Oct 22;285(43):33054-33064. doi: 10.1074/jbc.M110.162081.
Michael L Booker 1,  Cecilia M Bastos 2,  Martin L Kramer 2,  Robert H Barker Jr 2,  Renato Skerlj 2,  Amar Bir Sidhu 3,  Xiaoyi Deng 4,  Cassandra Celatka 2,  Joseph F Cortese 3,  Jose E Guerrero Bravo 5,  Keila N Crespo Llado 5,  Adelfa E Serrano 5,  Iñigo Angulo-Barturen 6,  María Belén Jiménez-Díaz 6,  Sara Viera 6,  Helen Garuti 6,  Sergio Wittlin 7,  Petros Papastogiannidis 7,  Jing-Wen Lin 8,  Chris J Janse 8,  Shahid M Khan 8,  Manoj Duraisingh 9,  Bradley Coleman 9,  Elizabeth J Goldsmith 10,  Margaret A Phillips 4,  Benito Munoz 3,  Dyann F Wirth 9,  Jeffrey D Klinger 2,  Roger Wiegand 3,  Edmund Sybertz 2
Affiliations

Affiliations

  • 1 From Genzyme Corporation, Waltham, Massachusetts 02451. Electronic address: michael.booker@genzyme.com.
  • 2 From Genzyme Corporation, Waltham, Massachusetts 02451.
  • 3 Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141.
  • 4 Departments of Pharmacology, Dallas, Texas 75390-9041.
  • 5 Department of Microbiology and Medical Zoology, University of Puerto Rico School of Medicine, P. O. Box 365067, San Juan, Puerto Rico 00936-5067.
  • 6 Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
  • 7 Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003, Basel, Switzerland.
  • 8 Leiden Malaria Research Group, Department of Parasitology, Centre for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
  • 9 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115.
  • 10 Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041.
PMID: 20702404 DOI: 10.1074/jbc.M110.162081
Abstract

Plasmodium falciparum, the causative agent of the most deadly form of human malaria, is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. Dihydroorotate Dehydrogenase (DHODH) catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and represents a potential target for anti-malarial therapy. A high throughput screen and subsequent medicinal chemistry program identified a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH from P. falciparum, P. vivax, and P. berghei. The compounds were selective for the Parasite enzymes over human DHODH, and x-ray structural data on the analog Genz-667348, demonstrated that species selectivity could be attributed to amino acid differences in the inhibitor-binding site. Compounds from this series demonstrated in vitro potency against the 3D7 and Dd2 strains of P. falciparum, good tolerability and oral exposure in the mouse, and ED(50) values in the 4-day murine P. berghei efficacy model of 13-21 mg/kg/day with oral twice-daily dosing. In particular, treatment with Genz-667348 at 100 mg/kg/day resulted in sterile cure. Two recent analogs of Genz-667348 are currently undergoing pilot toxicity testing to determine suitability as clinical development candidates.

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