Novel echinocandin antifungals. Part 2: Optimization of the side chain of the natural product FR901379. Discovery of micafungin.
Further optimization of the potent antifungal activity of side chain analogs of the natural product FR901379 led to the discovery of compound 8 with an excellent, well-balanced profile. Potent compounds with reduced hemolytic potential were designed based upon a disruption of the linearity of the terphenyl lipophilic side chain. The optimized compound (8, FK463, micafungin) displayed the best balance and was selected as the clinical candidate.
Tomishima
Masaki
M
Medicinal Chemistry Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. masaki.tomishima@jp.astellas.com
Ohki
Hidenori
H
Yamada
Akira
A
Maki
Katsuyuki
K
Ikeda
Fumiaki
F
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D001688:Biological Products / Q000138:chemical synthesis / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D054714:Echinocandins / Q000138:chemical synthesis / Q000494:pharmacology*; D055666:Lipopeptides; D008074:Lipoproteins; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001688:Biological Products; D054714:Echinocandins; C110368:FR 901379; D055666:Lipopeptides; D008074:Lipoproteins; D010456:Peptides, Cyclic; D000077551:Micafungin