Pharmacological Characterization of [<i>trans</i>-5′-(4-Amino-7,7-dimethyl-2-trifluoromethyl-7<i>H</i>-pyrimido[4,5-<i>b</i>][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
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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 [<i>trans</i>-5′-(4-amino-7,7-dimethyl-2-trifluoromethyl-7<i>H</i>-pyrimido[4,5-<i>b</i>][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 [<sup>14</sup>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. <i>In vivo</i>, 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 [<sup>14</sup>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.
- Biological and Pharmaceutical Bulletin
Biological and Pharmaceutical Bulletin 38(2), 263-269, 2015
The Pharmaceutical Society of Japan