Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series.
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1. nicolas.lachance21@gmail.com
Nicolas
N
Lachance
Yves
Y
Gareau
Sébastien
S
Guiral
Zheng
Z
Huang
Elise
E
Isabel
Jean-Philippe
JP
Leclerc
Serge
S
Léger
Evelyn
E
Martins
Christian
C
Nadeau
Renata M
RM
Oballa
Stéphane G
SG
Ouellet
David A
DA
Powell
Yeeman K
YK
Ramtohul
Geoffrey K
GK
Tranmer
Thao
T
Trinh
Hao
H
Wang
Lei
L
Zhang
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D013230:Stearoyl-CoA Desaturase