Identification of a broad-spectrum azasordarin with improved pharmacokinetic properties.
The synthesis and antifungal activity of 5'- and 5'-6'-substituted azasordarin derivatives are described. Modification of the 5'-position led to the discovery of the spirocyclopentyl analogue 7g, which is the first azasordarin to register single-digit MIC values versus Aspergillus spp. Further investigation identified the 5'-i-Pr derivative 7b, which displays superior pharmacokinetic properties compared to other azasordarins.
Serrano-Wu
Michael H
MH
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. michael.serrano-wu@bms.com
Laurent
Denis R St
DR
Carroll
Tina M
TM
Dodier
Marco
M
Gao
Qi
Q
Gill
Patrice
P
Quesnelle
Claude
C
Marinier
Anne
A
Mazzucco
Charles E
CE
Regueiro-Ren
Alicia
A
Stickle
Terry M
TM
Wu
Dedong
D
Yang
Hyekyung
H
Yang
Zheng
Z
Zheng
Ming
M
Zoeckler
Mary E
ME
Vyas
Dolatrai M
DM
Balasubramanian
Balu N
BN
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001230:Aspergillus / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006027:Glycosides / Q000737:chemistry; D007192:Indenes; D007275:Injections, Intravenous; D051379:Mice; D008826:Microbial Sensitivity Tests; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001372:Aza Compounds; D006027:Glycosides; D007192:Indenes; D013141:Spiro Compounds; C003329:sordarin