Cetilistat (ATL-962)   中文名称: 新利司他

The target of Cetilistat (ATL-962) is pancreatic lipase. It inhibits rat pancreatic lipase with an IC₅₀ of 54.8 nmol/l and human pancreatic lipase with an IC₅₀ of 5.95 nmol/l, showing 9.2 times higher potency against human pancreatic lipase than rat pancreatic lipase[1]

cetilistat 抑制大鼠胰腺脂肪酶活性，IC50 为 54.8 nM。此外，cetilistat 对人胰腺脂肪酶活性的抑制作用是大鼠胰腺脂肪酶的 9.2 倍，IC50 为 5.95 nM[1]。

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西替利司他（Cetilistat，ATL-962）的体外活性主要体现在对胰脂肪酶的抑制作用上。实验表明，西替利司他（Cetilistat，ATL-962）能够抑制大鼠胰脂肪酶活性，其IC₅₀值为54.8 nmol/l；同时也能抑制人胰脂肪酶活性，且IC₅₀值更低，为5.95 nmol/l。这说明西替利司他（Cetilistat，ATL-962）在体外对胰脂肪酶具有较强的抑制作用，且对人胰脂肪酶的抑制效果显著强于对大鼠胰脂肪酶的抑制效果[1]

在雄性 SD 大鼠中，cetilistat（3、10、30 或 100 mg/kg）抑制胰腺脂肪酶活性，减少肠道脂肪吸收[1]。通过减少肠道脂肪吸收，西替司他（4.9、14.9或50.7 mg/kg；混入粉状高脂食品中；每天三次；持续三周）对DIO F344大鼠具有抗肥胖和降高脂作用[1]。

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1. 对Sprague-Dawley大鼠血浆甘油三酯（TG）浓度的影响：将西替利司他（Cetilistat，ATL-962）与脂肪乳剂同时经口给予Sprague-Dawley大鼠，给药剂量分别为3、10、30和100 mg/kg。结果显示，西替利司他（Cetilistat，ATL-962）能以剂量依赖性方式降低经口脂肪负荷引起的血浆甘油三酯浓度升高，表明其可减少大鼠肠道脂肪吸收[1]
2. 对饮食诱导肥胖（DIO）F344大鼠的影响：将西替利司他（Cetilistat，ATL-962）作为食物添加剂混入高脂饲料中，以4.9、14.9和50.7 mg/kg/天的剂量给DIO F344大鼠给药，持续三周。结果发现，大鼠粪便中甘油三酯和非酯化脂肪酸含量呈剂量依赖性显著增加，提示西替利司他（Cetilistat，ATL-962）可促进肠道脂肪的分解和排泄。同时，大鼠的体重（BW）增长和白色脂肪组织（WAT）重量均呈剂量依赖性降低。此外，大鼠血浆中的瘦素、甘油三酯（TG）和总胆固醇（TC）水平也有所降低，且未出现油性粪便的报告[1]

针对西替利司他（Cetilistat，ATL-962）的酶活性测定主要围绕其对胰脂肪酶的抑制作用展开，具体流程如下：首先，制备含有大鼠或人胰脂肪酶以及相应底物的反应体系；然后，向反应体系中加入不同浓度的西替利司他（Cetilistat，ATL-962），并设置不含西替利司他（Cetilistat，ATL-962）的对照组；将反应体系在适宜的温度和时间条件下孵育后，通过相关检测方法（如分光光度法）检测体系中底物或产物浓度的变化，以此反映胰脂肪酶的活性；最后，根据不同药物浓度下酶活性的变化情况，计算出西替利司他（Cetilistat，ATL-962）对大鼠和人胰脂肪酶抑制作用的IC₅₀值[1]

Animal/Disease Models: Fifty male SD rats (eight weeks of age)[1]
Doses: 3, 10 , 30, or 100 mg/kg
Route of Administration: Orally administered; prepared in 0.5 % methylcellulose (MC) suspension
Experimental Results: Dose-dependently decreased AUC 0-6 h of plasma triglyceride induced by oral loading of Intrafat 20%. The effect was statistically significant at 3 mg/kg, reaching 45% reduction, while an almost 90 % reduction was achieved at 100 mg/kg.

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Animal/Disease Models: Male diet-induced obesity (DIO) F344 rats (five weeks of age)[1]
Doses: 4.9 , 14.9, or 50.7 mg/kg
Route of Administration: Administered as food admixture in a high-fat diet; one time/day; for three weeks
Experimental Results: Dramatically and dose-dependently decreased body weight gain compared with control.

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1. Animal experiment on Sprague-Dawley rats (to observe the effect on plasma triglyceride concentration): Select Sprague-Dawley rats as experimental animals. Cetilistat (ATL-962) is orally administered to the rats simultaneously with fat emulsion. The doses of Cetilistat (ATL-962) are set as 3, 10, 30, and 100 mg/kg. Before and after oral fat loading, collect blood samples from the rats to measure the plasma triglyceride (TG) concentration, so as to evaluate the effect of Cetilistat (ATL-962) on reducing the elevation of plasma triglyceride caused by fat loading[1]
2. Animal experiment on DIO F344 rats (to observe the anti-obesity and lipid-lowering effects): Use diet-induced obesity (DIO) F344 rats as experimental models. Cetilistat (ATL-962) is mixed into a high-fat diet as a food admixture and administered to the rats. The doses are 4.9, 14.9, and 50.7 mg/kg/day, and the administration lasts for three weeks. During the experiment, regularly record the body weight of the rats. After the experiment, collect feces to detect the content of triglyceride and nonesterified fatty acid, dissect the rats to take white adipose tissue (WAT) and weigh it, and collect blood samples to measure plasma levels of leptin, triglyceride (TG), and total cholesterol (TC)[1]

[1]. Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats. Horm Metab Res. 2008 Aug;40(8):539-43.

Cetilistat is a benzoxazine.
Cetilistat is a novel inhibitor of pancreatic lipase being developed by Alizyme for the treatment of obesity and associated co-morbidities, including type 2 diabetes.

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Drug Indication
Investigated for use/treatment in obesity.

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Mechanism of Action
Cetilistat is a gastrointestinal lipase inhibitor that blocks fat digestion and absorption, leading to reduced energy intake, and thus weight loss. It is distinct from most other anti-obesity agents as it does not act on the brain to reduce appetite, but acts peripherally. The compound remains in the gastrointestinal tract with no significant absorption into the body.

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Cetilistat (ATL-962) is a novel pancreatic lipase inhibitor. Pancreatic lipase is an important enzyme involved in intestinal fat digestion and absorption. By inhibiting the activity of pancreatic lipase, Cetilistat (ATL-962) can reduce the digestion and absorption of fat in the intestine, thereby reducing the intake of fat calories, which in turn plays a role in ameliorating body weight gain and improving lipid profiles. The experimental results in diet-induced obesity (DIO) rats (a plausible animal model of the most common type of human obesity) show that Cetilistat (ATL-962) has the potential to ameliorate obesity and hyperlipidemia, providing a basis for its further research and development in the field of anti-obesity and lipid-lowering[1]

C25H39NO3

401.58

401.292

282526-98-1

9952916

White to off-white solid powder

1.0±0.1 g/cm3

509.7±43.0 °C at 760 mmHg

74°C

158.9±22.6 °C

0.0±1.3 mmHg at 25°C

1.521

9.93

52.33

0

4

16

29

477

0

MVCQKIKWYUURMU-UHFFFAOYSA-N

InChI=1S/C25H39NO3/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-19-28-25-26-23-18-17-21(2)20-22(23)24(27)29-25/h17-18,20H,3-16,19H2,1-2H3

2-hexadecoxy-6-methyl-3,1-benzoxazin-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)