Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438).
A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders.
Léger
Serge
S
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire-Dorval, Québec, Canada H9R 4P8.
Black
W Cameron
WC
Deschenes
Denis
D
Dolman
Sarah
S
Falgueyret
Jean-Pierre
JP
Gagnon
Marc
M
Guiral
Sébastien
S
Huang
Zheng
Z
Guay
Jocelyne
J
Leblanc
Yves
Y
Li
Chun-Sing
CS
Massé
Frédéric
F
Oballa
Renata
R
Zhang
Lei
L
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; C548713:MF 438; D011724:Pyridazines; D013830:Thiadiazoles; C062482:pyridazine; D013230:Stearoyl-CoA Desaturase