Document Detail

Systematic Structure Modifications of Imidazo[1,2-a]pyrimidine to Reduce Metabolism Mediated by Aldehyde Oxidase (AO).
MedLine Citation:
PMID:  21955208     Owner:  NLM     Status:  Publisher    
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.
Maria Angelica Linton; Ping Kang; Martha Ornelas; Susan Kephart; Qiyue Hu; Mason Pairish; Ying Jiang; Chuangxing Guo
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-9-28
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-9-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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