title: Discovery of WQ-3810: Design, synthesis, and evaluation of 7-(3-alkylaminoazetidin-1-yl)fluoro-quinolones as orally active antibacterial agents.
abstract: Novel 7-(3-alkylaminoazetidin-1-yl)fluoroquinolones were designed, synthesized, and evaluated for their antibacterial activities and oral absorption rates. Against Gram-negative bacteria, 10a-e, which have various alkyl groups containing different numbers of carbon atoms (C0-C3) at the C-7 alkylaminoazetidine position, showed potent and similar antibacterial activities, whereas the activity of 10f (C4, t-Bu) was significantly lower than those of 10a-e. Conversely, the oral absorption rates of 10a-e in rats increased depending on the number of carbon atoms in the alkyl groups; 10d (C3, n-Pr) and 10e (C3, i-Pr) had high oral absorption rates (>90% at 10 mg/kg). These results demonstrated that the introduction of alkyl groups onto C-7 aminoazetidine is useful for the improvement of the oral absorption rates of these drugs while maintaining their antibacterial activities. As a conclusion, from this series of fluoroquinolones, WQ-3810 (10e), having 3-isopropylaminoazetidine as the C-7 substituent, was identified as an orally active antibacterial agent with a potent in vitro activity.
authors.affiliation: Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima 739-1195, Japan. Electronic address: itoh_k@wakunaga.co.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima 739-1195, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuramoto
authors.affiliation: Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima 739-1195, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Amano
authors.affiliation: Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima 739-1195, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Kazamori
authors.affiliation: Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd., 1624 Shimokotachi, Koda-cho, Akitakata-shi, Hiroshima 739-1195, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yazaki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001384:Azetidines; D024841:Fluoroquinolones; C000607149:WQ-3810
keywords: Alkylaminoazetidine; Antibacterial agent; Fluoroquinolone; Gram-negative bacteria; Oral absorption