title: Quinolone carboxylic acids as a novel monoketo acid class of human immunodeficiency virus type 1 integrase inhibitors.
abstract: 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.
authors.affiliation: Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
authors.forename: Motohide
authors.initials: M
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawakami
authors.forename: Takahisa
authors.initials: T
authors.lastname: Motomura
authors.forename: Hisateru
authors.initials: H
authors.lastname: Aramaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Ito
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzaki
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Yamataka
authors.forename: Satoru
authors.initials: S
authors.lastname: Ikeda
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shinkai
mesh_terms: D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D015363:Quinolones; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1