title: Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model.
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.
authors: From Genzyme Corporation, Waltham, Massachusetts 02451. Electronic address: michael.booker@genzyme.com.
authors: Michael L
authors: ML
authors: Booker
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Cecilia M
authors: CM
authors: Bastos
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Martin L
authors: ML
authors: Kramer
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Robert H
authors: RH
authors: Barker
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Renato
authors: R
authors: Skerlj
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141.
authors: Amar Bir
authors: AB
authors: Sidhu
authors: Departments of Pharmacology, Dallas, Texas 75390-9041.
authors: Xiaoyi
authors: X
authors: Deng
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Cassandra
authors: C
authors: Celatka
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141.
authors: Joseph F
authors: JF
authors: Cortese
authors: Department of Microbiology and Medical Zoology, University of Puerto Rico School of Medicine, P. O. Box 365067, San Juan, Puerto Rico 00936-5067.
authors: Jose E
authors: JE
authors: Guerrero Bravo
authors: Department of Microbiology and Medical Zoology, University of Puerto Rico School of Medicine, P. O. Box 365067, San Juan, Puerto Rico 00936-5067.
authors: Keila N
authors: KN
authors: Crespo Llado
authors: Department of Microbiology and Medical Zoology, University of Puerto Rico School of Medicine, P. O. Box 365067, San Juan, Puerto Rico 00936-5067.
authors: Adelfa E
authors: AE
authors: Serrano
authors: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Iñigo
authors: I
authors: Angulo-Barturen
authors: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: María Belén
authors: MB
authors: Jiménez-Díaz
authors: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Sara
authors: S
authors: Viera
authors: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors: Helen
authors: H
authors: Garuti
authors: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003, Basel, Switzerland.
authors: Sergio
authors: S
authors: Wittlin
authors: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003, Basel, Switzerland.
authors: Petros
authors: P
authors: Papastogiannidis
authors: Leiden Malaria Research Group, Department of Parasitology, Centre for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Jing-Wen
authors: JW
authors: Lin
authors: Leiden Malaria Research Group, Department of Parasitology, Centre for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Chris J
authors: CJ
authors: Janse
authors: Leiden Malaria Research Group, Department of Parasitology, Centre for Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Shahid M
authors: SM
authors: Khan
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115.
authors: Manoj
authors: M
authors: Duraisingh
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115.
authors: Bradley
authors: B
authors: Coleman
authors: Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041.
authors: Elizabeth J
authors: EJ
authors: Goldsmith
authors: Departments of Pharmacology, Dallas, Texas 75390-9041.
authors: Margaret A
authors: MA
authors: Phillips
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141.
authors: Benito
authors: B
authors: Munoz
authors: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115.
authors: Dyann F
authors: DF
authors: Wirth
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Jeffrey D
authors: JD
authors: Klinger
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02141.
authors: Roger
authors: R
authors: Wiegand
authors: From Genzyme Corporation, Waltham, Massachusetts 02451.
authors: Edmund
authors: E
authors: Sybertz
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002460:Cell Line; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010962:Plasmodium berghei / Q000201:enzymology; D010963:Plasmodium falciparum / Q000201:enzymology*; D010966:Plasmodium vivax / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015800:Protozoan Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors