Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: discovery of FR264205.
We describe herein the synthesis and biological evaluation of a series of novel cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led to the discovery of FR264205 (15) with excellent anti-bacterial activity and weak convulsion effect by direct intracerebroventricular injection assay.
Toda
Ayako
A
Chemistry Research Labs, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan.
Ohki
Hidenori
H
Yamanaka
Toshio
T
Murano
Kenji
K
Okuda
Shinya
S
Kawabata
Kohji
K
Hatano
Kazuo
K
Matsuda
Keiji
K
Misumi
Keiji
K
Itoh
Kenji
K
Satoh
Kenji
K
Inoue
Satoshi
S
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D051379:Mice; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D012640:Seizures / Q000139:chemically induced; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C519491:ceftolozane; D002442:Ceftazidime