title: Systematic structure modifications of imidazo[1,2-a]pyrimidine to reduce metabolism mediated by aldehyde oxidase (AO).
abstract: N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.
authors.affiliation: Pfizer Worldwide Research & Development, San Diego, CA 92121, USA. angelica.linton@pfizer.com
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Ping
authors.initials: P
authors.lastname: Kang
authors.forename: Martha
authors.initials: M
authors.lastname: Ornelas
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
mesh_terms: D042931:Aldehyde Oxidase / Q000737:chemistry* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry*; D020134:Catalytic Domain; D003503:Cyclobutanes / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D003503:Cyclobutanes; D007093:Imidazoles; C569677:N-(3-((5-cyano-6-methylpyridin-2-yl)oxy)-2,2,4,4-tetramethylcyclobutyl)imidazo(1,2-a)pyrimidine-3-carboxamide; D011743:Pyrimidines; D042931:Aldehyde Oxidase