title: Falcipain inhibitors: optimization studies of the 2-pyrimidinecarbonitrile lead series.
abstract: Falcipain-2 and falcipain-3 are papain-family cysteine proteases of the malaria parasite Plasmodium falciparum that are responsible for host hemoglobin hydrolysis to provide amino acids for parasite protein synthesis. Different heteroarylnitrile derivatives were studied as potential falcipain inhibitors and therefore potential antiparasitic lead compounds, with the 5-substituted-2-cyanopyrimidine chemical class emerging as the most potent and promising lead series. Through a sequential lead optimization process considering the different positions present in the initial scaffold, nanomolar and subnanomolar inhibitors at falcipains 2 and 3 were identified, with activity against cultured parasites in the micromolar range. Introduction of protonable amines within lead molecules led to marked improvements of up to 1000 times in activity against cultured parasites without noteworthy alterations in other SAR tendencies. Optimized compounds presented enzymatic activities in the picomolar to low nanomolar range and antiparasitic activities in the low nanomolar range.
authors.affiliation: Department of Drug Discovery Chemistry, GlaxoSmithKline, Madrid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Coterón
authors.forename: David
authors.initials: D
authors.lastname: Catterick
authors.forename: Julia
authors.initials: J
authors.lastname: Castro
authors.forename: María J
authors.initials: MJ
authors.lastname: Chaparro
authors.forename: Beatriz
authors.initials: B
authors.lastname: Díaz
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gamo
authors.forename: Mariola
authors.initials: M
authors.lastname: Gordo
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Laura
authors.initials: L
authors.lastname: de las Heras
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.forename: Maria
authors.initials: M
authors.lastname: Marco
authors.forename: Juan
authors.initials: J
authors.lastname: Miguel
authors.forename: Vicente
authors.initials: V
authors.lastname: Muñoz
authors.forename: Esther
authors.initials: E
authors.lastname: Porras
authors.forename: Juan C
authors.initials: JC
authors.lastname: de la Rosa
authors.forename: Jose R
authors.initials: JR
authors.lastname: Ruiz
authors.forename: Elena
authors.initials: E
authors.lastname: Sandoval
authors.forename: Pilar
authors.initials: P
authors.lastname: Ventosa
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Jose M
authors.initials: JM
authors.lastname: Fiandor
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3