title: Orally active cephalosporins. Part 4: synthesis, structure--activity relationships and oral absorption of novel 3-(4-pyrazolylmethylthio)cephalosporins with various C-7 side chains.
abstract: A series of 3-(4-pyrazolylmethylthio)cephalosporins with various C-7 side chains was designed, synthesized and evaluated for antibacterial activity and oral absorption in rats. Antibacterial activity against Haemophilus influenzae was markedly increased by the C-7 oxime moiety. Deamination at the 2 position of, or introduction of a substituent such as halogen or methyl to, the 5 position of the (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) moiety improved oral absorption. Among these compounds, FR192752 having a (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetamido moiety, showed potent antibacterial activity against both Gram-positive and Gram-negative bacteria including H.influenzae and penicillin G-resistant Streptococcus pneumoniae (PRSP). Further, it showed higher oral absorption than CFDN and FK041.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, 532-8514, Osaka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Eikyu
authors.forename: Shinya
authors.initials: S
authors.lastname: Okuda
authors.forename: Kohji
authors.initials: K
authors.lastname: Kawabata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takasugi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tawara
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001646:Bile; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014556:Urine
chemical_list: D002511:Cephalosporins