Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential Articles uri icon

authors

  • COTERON, JOSE M.
  • MARCO, MARIA
  • 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, ÍÑIGO
  • FERRER BAZAGA, SANTIAGO
  • 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.

publication date

  • August 2011

start page

  • 5540

end page

  • 5561

issue

  • 15

volume

  • 54

International Standard Serial Number (ISSN)

  • 0022-2623

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

abstract

  • 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.

subjects

  • Biology and Biomedicine
  • Medicine

keywords

  • inhibitors; parasites; peptides and proteins; pharmacokinetics; rodent models