Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors.
A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure-activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.
Xin
Zhili
Z
Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Road, Abbott Park, IL 60064, USA. zhili.xin@biogenidec.com
Zhao
Hongyu
H
Serby
Michael D
MD
Liu
Bo
B
Liu
Mei
M
Szczepankiewicz
Bruce G
BG
Nelson
Lissa T J
LT
Smith
Harriet T
HT
Suhar
Tom S
TS
Janis
Rich S
RS
Cao
Ning
N
Camp
Heidi S
HS
Collins
Christine A
CA
Sham
Hing L
HL
Surowy
Teresa K
TK
Liu
Gang
G
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C530575:4-(2-chlorophenoxy)-N-(3-(methyl carbamoyl)phenyl)piperidine-1-carboxamide; D004791:Enzyme Inhibitors; D010880:Piperidines; D014508:Urea; D013230:Stearoyl-CoA Desaturase