title: Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.
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.
authors.affiliation: GlaxoSmithKline, Diseases of the Developing World (DDW)-Tres Cantos Medicines Development Campus, Madrid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Coteron
authors.forename: María
authors.initials: M
authors.lastname: Marco
authors.forename: Jorge
authors.initials: J
authors.lastname: Esquivias
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Maria
authors.initials: M
authors.lastname: Koltun
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
authors.forename: Kasiram
authors.initials: K
authors.lastname: Katneni
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhamidipati
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: Santiago B
authors.initials: SB
authors.lastname: Ferrer
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Goldsmith
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: David
authors.initials: D
authors.lastname: Floyd
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D004351:Drug Resistance; D006801:Humans; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000201:enzymology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D011743:Pyrimidines; D014230:Triazoles; D044925:Oxidoreductases Acting on CH-CH Group Donors