SAR and optimization of thiazole analogs as potent stearoyl-CoA desaturase inhibitors.
Elevated stearoyl-CoA desaturase (SCD) activity has been linked to a number of metabolic disorders including obesity and type II diabetes. Compound 3j, a potent SCD inhibitor (human HepG2 IC(50)=1nM) was identified from the optimization of a lead thiazole compound MF-152 with over 100-fold improvement in potency. In a 4-week chronic oral dosing at 0.2mg/kg, 3j gave a robust 24% prevention of body weight gain in mice fed on a high fat diet accompanied with an improved metabolic profile on insulin and glucose levels.
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1. yeeman_ramtohul@merck.com
Yeeman K
YK
Ramtohul
Cameron
C
Black
Chi-Chung
CC
Chan
Sheldon
S
Crane
Jocelyne
J
Guay
Sébastien
S
Guiral
Zheng
Z
Huang
Renata
R
Oballa
Li-Jing
LJ
Xu
Lei
L
Zhang
Chun Sing
CS
Li
D000284:Administration, Oral; D000818:Animals; D004041:Dietary Fats; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015430:Weight Gain
D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; D013844:Thiazoles; D013230:Stearoyl-CoA Desaturase