Pharmacological characterization of [trans-5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate (JTT-553), a novel acyl CoA:diacylglycerol transferase (DGAT) 1 inhibitor.
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 is an enzyme that catalyzes the final step in triglyceride (TG) synthesis. This enzyme is considered to be a potential therapeutic target for obesity and diabetes. Here, results of an investigation of the pharmacological effects of JTT-553 [trans-5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl]acetic acid monobenzenesulfonate, a novel DGAT1 inhibitor, are reported. To measure the inhibitory activity of JTT-553 against DGAT1, TG synthesis using [(14)C]-labeled oleoyl-CoA was evaluated. Similarly, the inhibitory activity of JTT-553 against DGAT2, an isozyme of DGAT1, and acyl-CoA cholesterol acyltransferase (ACAT) 1, which is highly homologous to DGAT1, were evaluated. JTT-553 selectively inhibited human DGAT1 and showed comparable inhibitory effects on the activity of human, rat, and mouse DGAT. In vivo, JTT-553 suppressed plasma TG and chylomicron TG levels after olive oil loading in Sprague-Dawley (SD) rats. JTT-553 also inhibited TG synthesis in epididymal fat after [(14)C] oleic acid injection in C57BL/6J mice. Food intake was evaluated in SD rats fed 3.1%, 13%, or 35% (w/w) fat diets. In rats fed the 35% fat diet, JTT-553 reduced food intake. This reduction of food intake was observed 2 h after feeding, lasted for 24 h, and correlated with dietary fat content. Furthermore, JTT-553 reduced daily food intake and body weight gain in diet-induced obese rats after 4-week repeated administration. JTT-553 exerted multiple effects on intestinal fat absorption, adipose fat synthesis, and food intake, and consequently induced body weight reduction. Therefore, JTT-553 is expected to be an effective novel therapeutic agent for the treatment of obesity.
Central Pharmaceutical Research Institute, Japan Tobacco Inc.
Daisuke
D
Tomimoto
Chihiro
C
Okuma
Yukihito
Y
Ishii
Yoshiyuki
Y
Akiyama
Takeshi
T
Ohta
Makoto
M
Kakutani
Yoshiaki
Y
Ohkuma
Nobuya
N
Ogawa
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004435:Eating; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010078:Oxazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
C000603501:(5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido(4,5-b)(1,4)oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl)acetic acid; D004791:Enzyme Inhibitors; D010078:Oxazines; D013141:Spiro Compounds; D014280:Triglycerides; C494881:DGAT1 protein, human; C494882:Dgat1 protein, mouse; C494883:Dgat1 protein, rat; D051048:Diacylglycerol O-Acyltransferase