Lead optimization of a sulfonylurea-based piperazine pyridazinone series of glucan synthase inhibitors.
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Medicinal Chemistry Department, Albany Molecular Research, Inc. (AMRI), 26 Corporate Circle, Albany, NY 12203, USA.
Andrew J
AJ
Zych
Sang Q
SQ
Lam
David M
DM
Jenkins
R Jason
RJ
Herr
Pauline C
PC
Ting
Joe F
JF
Lee
Rongze
R
Kuang
Heping
H
Wu
David W
DW
Kim
Robert G
RG
Aslanian
Samuel
S
Wainhaus
Todd A
TA
Black
Anthony
A
Cacciapuoti
Paul M
PM
McNicholas
Yiming
Y
Xu
Scott S
SS
Walker
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D002175:Candida / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D007854:Lead / Q000737:chemistry*; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D011724:Pyridazines; D013453:Sulfonylurea Compounds; D000077489:Piperazine; D007854:Lead; C062482:pyridazine; D005964:Glucosyltransferases; C040232:glucan synthase