Investigating amine derivatives of ambruticin VS-5 and VS-4.
A structure-activity relationship around the amine group of the ambruticin VS series has been developed for antifungal activity. It was shown that the amine can be alkylated through reductive amination without loss of potency. However, if it is converted into either an amide, carbamate, or urea, a significant loss of potency is observed. Of the alkyl amines, small nonpolar groups are optimal for both potency and oral bioavailability. As a result of this study, one compound (KOS-2079) was taken into an animal efficacy model with success.
Tian
Zong-Qiang
ZQ
Department of Chemistry, Kosan Biosciences, Inc. 3832 Bay Center Place, Hayward, CA 95454, USA.
Wang
Zhan
Z
Xu
Yuan
Y
Tran
Chau Q
CQ
Myles
David C
DC
Zhong
Ziyang
Z
Simmons
Jessica
J
Vetcher
Leandro
L
Katz
Leonard
L
Li
Yong
Y
Shaw
Simon J
SJ
D000478:Alkylation; D000586:Amination; D000588:Amines / Q000737:chemistry*; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D003045:Coccidioides / Q000187:drug effects*; D015195:Drug Design; D051379:Mice; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D000935:Antifungal Agents; D011714:Pyrans; C014964:ambruticin