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Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria. 2011
Renato T Skerlj, and
Cecilia M Bastos, and
Michael L Booker, and
Martin L Kramer, and
Robert H Barker, and
Cassandra A Celatka, and
Thomas J O'Shea, and
Benito Munoz, and
Amar Bir Sidhu, and
Joseph F Cortese, and
Sergio Wittlin, and
Petros Papastogiannidis, and
Inigo Angulo-Barturen, and
Maria Belen Jimenez-Diaz, and
Edmund Sybertz
Genzyme Corporation , 153 Second Avenue, Waltham, Massachusetts 02451, United States.
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.
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