title: Evaluation of the metabolism, bioactivation and pharmacokinetics of triaminopyrimidine analogs toward selection of a potential candidate for antimalarial therapy.
abstract: 1. During the course of metabolic profiling of lead Compound 1, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and N-acetylcysteine (NAC) conjugates in microsomal incubations. 2. It was proposed that bioactivation of Compound 1 occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core. 3. To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC. 4. Compounds 1 and 2, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates in vitro, whereas compounds with tertiary nitrogens at C-5 (Compound 3 and 4) formed no such conjugates. 5. These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound 3 and 4 incapable of forming thiol conjugates. 6. This finding enabled advancement of compound 4, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.
authors.affiliation: a Safety and ADME Translational Sciences, Drug Safety and Metabolism IMED, AstraZeneca plc , Cambridge , United Kingdom of Great Britain and Northern Ireland.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: b Infection IMED, AstraZeneca India Pvt. Ltd , Bangalore , India , and.
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
authors.affiliation: b Infection IMED, AstraZeneca India Pvt. Ltd , Bangalore , India , and.
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.affiliation: b Infection IMED, AstraZeneca India Pvt. Ltd , Bangalore , India , and.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: K R
authors.affiliation: b Infection IMED, AstraZeneca India Pvt. Ltd , Bangalore , India , and.
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed
authors.affiliation: b Infection IMED, AstraZeneca India Pvt. Ltd , Bangalore , India , and.
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.affiliation: c AstraZeneca Neuroscience Innovative Medicines , Cambridge , MA , USA.
authors.forename: Vinayak P
authors.initials: VP
authors.lastname: Hosagrahara
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D011809:Quinones; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D000962:Antimalarials; D011809:Quinones; D013438:Sulfhydryl Compounds; C116897:iminoquinone; D005978:Glutathione; D000111:Acetylcysteine
keywords: Bioactivation; LC-MS; N-acetylcysteine conjugate-reactive metabolite; glutathione conjugate; metabolite profiling; pharmacokinetics