title: Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria.
abstract: Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Bastos
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Booker
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Kramer
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Barker
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Celatka
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Shea
authors.affiliation: Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02141, United States.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02141, United States.
authors.forename: Amar Bir
authors.initials: AB
authors.lastname: Sidhu
authors.affiliation: Broad Institute of Harvard and MIT , Cambridge, Massachusetts 02141, United States.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cortese
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002, Basel, Switzerland ; University of Basel , Petersplatz 1, CH-4003, Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Swiss Tropical and Public Health Institute , Socinstrasse 57, CH-4002, Basel, Switzerland ; University of Basel , Petersplatz 1, CH-4003, Basel, Switzerland.
authors.forename: Petros
authors.initials: P
authors.lastname: Papastogiannidis
authors.affiliation: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Inigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline , c/Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Jimenez-Diaz
authors.affiliation: Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
authors.forename: Edmund
authors.initials: E
authors.lastname: Sybertz
keywords: DHODH; P. falciparum; drug candidate; malaria