Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors.
Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
Liu
Gang
G
Metabolic Disease Research, Drug Metabolism, Advanced Technology, Exploratory Pharmacokinetics, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6101, USA. liugx@gmail.com
Lynch
John K
JK
Freeman
Jennifer
J
Liu
Bo
B
Xin
Zhili
Z
Zhao
Hongyu
H
Serby
Michael D
MD
Kym
Philip R
PR
Suhar
Tom S
TS
Smith
Harriet T
HT
Cao
Ning
N
Yang
Ruojing
R
Janis
Rich S
RS
Krauser
Joel A
JA
Cepa
Steven P
SP
Beno
David W A
DW
Sham
Hing L
HL
Collins
Christine A
CA
Surowy
Teresa K
TK
Camp
Heidi S
HS
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000214:Acyl Coenzyme A; C531040:CAY10566; D010069:Oxadiazoles; D011724:Pyridazines; C523776:SCD1 protein, human; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase