Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities.
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Tang
Haifeng
H
Department of Medicinal Chemistry, Metabolic Disorders, Drug Metabolism and Pharmacology, Merck Research Laboratories, Rahway, NJ 07065, USA. haifeng_tang@merck.com
Yan
Yan
Y
Feng
Zhe
Z
de Jesus
Reynalda K
RK
Yang
Lihu
L
Levorse
Dorothy A
DA
Owens
Karen A
KA
Akiyama
Taro E
TE
Bergeron
Raynald
R
Castriota
Gino A
GA
Doebber
Thomas W
TW
Ellsworth
Kenneth P
KP
Lassman
Michael E
ME
Li
Cai
C
Wu
Margaret S
MS
Zhang
Bei B
BB
Chapman
Kevin T
KT
Mills
Sander G
SG
Berger
Joel P
JP
Pasternak
Alexander
A
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D020005:Propanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006845:Hydrocarbons, Fluorinated
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D002262:Carboxy-Lyases; D007004:Hypoglycemic Agents; D020005:Propanols; D013844:Thiazoles; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated; C021532:malonyl-CoA decarboxylase