Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.
Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.
Goodman
Krista B
KB
Department of Chemistry, Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, UW2430, King of Prussia, PA 19406, USA. krista.b.goodman@gsk.com
Bury
Michael J
MJ
Cheung
Mui
M
Cichy-Knight
Maria A
MA
Dowdell
Sarah E
SE
Dunn
Allison K
AK
Lee
Dennis
D
Lieby
Jeffrey A
JA
Moore
Michael L
ML
Scherzer
Daryl A
DA
Sha
Deyou
D
Suarez
Dominic P
DP
Murphy
Dennis J
DJ
Harpel
Mark R
MR
Manas
Eric S
ES
McNulty
Dean E
DE
Annan
Roland S
RS
Matico
Rosalie E
RE
Schwartz
Benjamin K
BK
Trill
John J
JJ
Sweitzer
Thomas D
TD
Wang
Da-Yuan
DY
Keller
Paul M
PM
Krawiec
John A
JA
Jaye
Michael C
MC
D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004727:Endothelium / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005663:Furans; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005663:Furans; D013453:Sulfonylurea Compounds; D008049:Lipase