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