title: Structural modifications of a 3-methoxy-2-aminopyridine compound to reduce potential for mutagenicity and time-dependent drug-drug interaction.
abstract: (S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.
authors.affiliation: Oncology Medicinal Chemistry, Pfizer PharmaTherapeutics R&D, San Diego, CA 92121, USA. cindy.palmer@pfizer.com
authors.forename: Cynthia
authors.initials: C
authors.lastname: Palmer
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Djamal
authors.initials: D
authors.lastname: Bouzida
authors.forename: Jingrong
authors.initials: J
authors.lastname: Cui
authors.forename: Judith
authors.initials: J
authors.lastname: Deal
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Danlin
authors.initials: D
authors.lastname: Gu
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Indrawan
authors.initials: I
authors.lastname: McAlpine
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Evan
authors.initials: E
authors.lastname: Smith
authors.forename: Annette
authors.initials: A
authors.lastname: John-Baptiste
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.forename: Robert
authors.initials: R
authors.lastname: Kania
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism; D004583:Electrons; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009152:Mutagenicity Tests; D010084:Oxidation-Reduction; D013997:Time Factors
chemical_list: C581083:3-methoxy-2-aminopyridine; D000631:Aminopyridines