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.
Ramtohul
Yeeman K
YK
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1. yeeman_ramtohul@merck.com
Black
Cameron
C
Chan
Chi-Chung
CC
Crane
Sheldon
S
Guay
Jocelyne
J
Guiral
Sébastien
S
Huang
Zheng
Z
Oballa
Renata
R
Xu
Li-Jing
LJ
Zhang
Lei
L
Li
Chun Sing
CS
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