Tomimoto Daisuke, Okuma Chihiro, Ishii Yukihito, Akiyama Yoshiyuki, Ohta Takeshi, Kakutani Makoto, Ohkuma Yoshiaki, Ogawa Nobuya
Central Pharmaceutical Research Institute, Japan Tobacco Inc.
Biol Pharm Bull. 2015;38(2):263-9. doi: 10.1248/bpb.b14-00655.
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.
酰基辅酶A：二酰基甘油酰基转移酶（DGAT）1是一种催化甘油三酯（TG）合成最后一步的酶。这种酶被认为是肥胖症和糖尿病的一个潜在治疗靶点。在此，报告了新型DGAT1抑制剂JTT - 553 [反式-5'-(4-氨基-7,7-二甲基-2-三氟甲基-7H-嘧啶并[4,5-b][1,4]恶嗪-6-基)-2',3'-二氢螺(环己烷-1,1'-茚)-4-基]乙酸单苯磺酸盐的药理作用研究结果。为了测定JTT - 553对DGAT1的抑制活性，使用[(14)C]标记的油酰辅酶A评估了TG合成。同样，评估了JTT - 553对DGAT1的同工酶DGAT2以及与DGAT1高度同源的酰基辅酶A胆固醇酰基转移酶（ACAT）1的抑制活性。JTT - 553选择性抑制人DGAT1，并且对人、大鼠和小鼠DGAT的活性表现出相当的抑制作用。在体内，JTT - 553抑制了Sprague - Dawley（SD）大鼠橄榄油负荷后的血浆TG和乳糜微粒TG水平。JTT - 553还抑制了C57BL/6J小鼠[(14)C]油酸注射后附睾脂肪中的TG合成。对喂食3.1%、13%或35%（w/w）脂肪饮食的SD大鼠的食物摄入量进行了评估。在喂食35%脂肪饮食的大鼠中，JTT - 553减少了食物摄入量。这种食物摄入量的减少在喂食后2小时观察到，持续24小时，并且与饮食脂肪含量相关。此外，在4周重复给药后，JTT - 553减少了饮食诱导肥胖大鼠的每日食物摄入量和体重增加。JTT - 553对肠道脂肪吸收、脂肪组织脂肪合成和食物摄入量产生多种影响，从而导致体重减轻。因此，JTT - 553有望成为治疗肥胖症的一种有效的新型治疗药物。
