Document Detail

Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors.
MedLine Citation:
PMID:  19719237     Owner:  NLM     Status:  MEDLINE    
Human immunodeficiency virus type 1 (HIV-1) integrase is a crucial target for antiretroviral drugs, and several keto-enol acid class (often referred to as diketo acid class) inhibitors have clinically exhibited marked antiretroviral activity. Here, we show the synthesis and the detailed structure-activity relationship of the quinolone carboxylic acids as a novel monoketo acid class of integrase inhibitors. 6-(3-Chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 51, which showed an IC50 of 5.8 nM in the strand transfer assay and an ED50 of 0.6 nM in the antiviral assay, and 6-(3-chloro-2-fluorobenzyl)-1-((2S)-1-hydroxy-3-methylbutan-2-yl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 49, which had an IC50 of 7.2 nM and an ED50 of 0.9 nM, were the most potent compounds in this class. The monoketo acid 49 was much more potent at inhibiting integrase-catalyzed strand transfer processes than 3'-processing reactions, as is the case with the keto-enol acids. Elvitegravir 49 was chosen as a candidate for further studies and is currently in phase 3 clinical trials.
Motohide Sato; Hiroshi Kawakami; Takahisa Motomura; Hisateru Aramaki; Takashi Matsuda; Masaki Yamashita; Yoshiharu Ito; Yuji Matsuzaki; Kazunobu Yamataka; Satoru Ikeda; Hisashi Shinkai
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-09-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4869-82     Citation Subset:  IM    
Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
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MeSH Terms
Carboxylic Acids / chemical synthesis*,  pharmacology
HIV Integrase / drug effects*
HIV Integrase Inhibitors / chemical synthesis*,  pharmacology
Quinolones / chemical synthesis*,  pharmacology
Structure-Activity Relationship
Reg. No./Substance:
0/Carboxylic Acids; 0/HIV Integrase Inhibitors; 0/Quinolones; 0/p31 integrase protein, Human immunodeficiency virus 1; EC 2.7.7.-/HIV Integrase

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