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Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

Coteron, Jose M ; Marco, María ; Esquivias, Jorge ; Deng, Xiaoyi ; White, Karen L ; White, John ; Koltun, Maria ; El Mazouni, Farah ; Kokkonda, Sreekanth ; Katneni, Kasiram ; Bhamidipati, Ravi ; Shackleford, David M ; Angulo-Barturen, Iñigo ; Ferrer, Santiago B ; Jiménez-Díaz, María Belén ; Gamo, Francisco-Javier ; Goldsmith, Elizabeth J ; Charman, William N ; Bathurst, Ian ; Floyd, David ; Matthews, David ; Burrows, Jeremy N ; Rathod, Pradipsinh K ; Charman, Susan A ; Phillips, Margaret A

Journal of medicinal chemistry, 2011-08, Vol.54 (15), p.5540-5561 [Periódico revisado por pares]

United States: American Chemical Society

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Título:
Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential
Autor: Coteron, Jose M ; Marco, María ; Esquivias, Jorge ; Deng, Xiaoyi ; White, Karen L ; White, John ; Koltun, Maria ; El Mazouni, Farah ; Kokkonda, Sreekanth ; Katneni, Kasiram ; Bhamidipati, Ravi ; Shackleford, David M ; Angulo-Barturen, Iñigo ; Ferrer, Santiago B ; Jiménez-Díaz, María Belén ; Gamo, Francisco-Javier ; Goldsmith, Elizabeth J ; Charman, William N ; Bathurst, Ian ; Floyd, David ; Matthews, David ; Burrows, Jeremy N ; Rathod, Pradipsinh K ; Charman, Susan A ; Phillips, Margaret A
Assuntos: 60 APPLIED LIFE SCIENCES ; Animals ; Antimalarials - chemical synthesis ; Antimalarials - pharmacology ; BASIC BIOLOGICAL SCIENCES ; Chemical Phenomena ; CHEMISTRY ; CLEARANCE ; Crystallography, X-Ray ; Drug Resistance ; HALF-LIFE ; Humans ; Mice ; OPTIMIZATION ; OXIDOREDUCTASES ; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors ; PLASMODIUM ; Plasmodium falciparum - enzymology ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Rats ; RODENTS ; STRAINS ; Structure-Activity Relationship ; THERAPY ; Triazoles - chemical synthesis ; Triazoles - chemistry ; Triazoles - pharmacokinetics ; Triazoles - pharmacology
É parte de: Journal of medicinal chemistry, 2011-08, Vol.54 (15), p.5540-5561
Notas: OTHERNIH
Descrição: Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.
Editor: United States: American Chemical Society
Idioma: Inglês

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Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

United States: American Chemical Society

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