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(Synonyms: 新利司他; ATL-962) 目录号 : GC31374

A pancreatic lipase inhibitor

Cetilistat (ATL-962) Chemical Structure

Cas No.:282526-98-1

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产品描述

Cetilistat is an inhibitor of pancreatic lipase (IC50s = 5.95 and 54.8 nM for the human and rat enzymes, respectively).1 It reduces increases in plasma triglyceride levels in an oral fat tolerance test, indicating decreased intestinal fat absorption, in rats when administered at a doses ranging from 3 to 100 mg/kg. Dietary administration of cetilistat (4.9-50.7 mg/kg per day) decreases body weight gain without affecting food intake, as well as reduces increases in plasma triglyceride and leptin levels in a rat model of high-fat diet-induced obesity. It also reduces viral load in the culture supernatant of Vero E6 cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; EC90 = 2.9 ?M) and inhibits SARS-CoV-2 replication in a plaque reduction assay (EC50 = 1.13 ?M).2

1.Yamada, Y., Kato, T., Ogino, H., et al.Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in ratsHorm. Metab. Res.40(8)539-543(2008) 2.Yuan, S., Chan, J.F.W., Chik, K.K.H., et al.Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening systemPharmacol. Res.159104960(2020)

Chemical Properties

Cas No. 282526-98-1 SDF
别名 新利司他; ATL-962
Canonical SMILES CC1=CC=C(N=C(OCCCCCCCCCCCCCCCC)OC2=O)C2=C1
分子式 C25H39NO3 分子量 401.58
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1 mM 2.4902 mL 12.4508 mL 24.9016 mL
5 mM 0.498 mL 2.4902 mL 4.9803 mL
10 mM 0.249 mL 1.2451 mL 2.4902 mL
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Research Update

Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon

Purpose of review: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity. This development is preceded by increased understanding of the underpinnings of energy regulation and neurohormonal pathways involved in energy homeostasis. Recent findings: Though there are approved anti-obesity drugs available in the USA, newer drugs are now in the pipeline for development given the urgent need. This review focuses on anti-obesity drugs in the pipeline including centrally acting agents (setmelanotide, neuropeptide Y antagonist [velneperit], zonisamide-bupropion [Empatic], cannabinoid type-1 receptor blockers), gut hormones and incretin targets (new glucagon-like-peptide-1 [GLP-1] analogues [semaglutide and oral equivalents], amylin mimetics [davalintide, dual amylin and calcitonin receptor agonists], dual action GLP-1/glucagon receptor agonists [oxyntomodulin], triple agonists [tri-agonist 1706], peptide YY, leptin analogues [combination pramlintide-metreleptin]), and other novel targets (methionine aminopeptidase 2 inhibitor [beloranib], lipase inhibitor [cetilistat], triple monoamine reuptake inhibitor [tesofensine], fibroblast growth factor 21), including anti-obesity vaccines (ghrelin, somatostatin, adenovirus36). With these new drugs in development, anti-obesity therapeutics have potential to vastly expand allowing better treatment options and personalized approach to obesity care.

Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients

Objective: To determine the efficacy, safety and tolerability of cetilistat (ATL-962), a novel inhibitor of gastrointestinal (GI) lipases, in obese patients.
Design: Phase II, multicentre, randomized, placebo-controlled, parallel group study. Enrolled patients (N=442) were advised a hypocaloric diet (deficient by 500 kcal per day, 30% of calories from fat) for a 2-week run-in period. Patients who satisfied the entry criteria (N=371) continued on the hypocaloric diet and were randomized to either placebo or one of three different doses of cetilistat (60 mg three times daily t.i.d., 120 mg t.i.d. and 240 mg t.i.d.) for 12 weeks, followed by a 4-week post-treatment follow-up. Safety, tolerability and body weight were assessed, together with other parameters associated with obesity.
Outcome measures: The primary outcome measure was absolute change in body weight from baseline. Secondary outcomes included the proportion of patients achieving pre-defined weight loss targets, changes from baseline in waist circumference and in blood lipids. GI tolerability criteria were specifically assessed, as was safety.
Results: Treatment with cetilistat reduced mean body weight to similar extents at all doses, which were statistically significant compared with placebo (60 mg t.i.d. 3.3 kg, P<0.03; 120 mg t.i.d. 3.5 kg, P=0.02; 240 mg t.i.d. 4.1 kg, P<0.001). Total serum and low-density lipoprotein cholesterol levels were likewise significantly reduced by 3-11% at all doses of cetilistat. Cetilistat was well tolerated. The frequency of withdrawal owing to treatment-emergent adverse events was similar between cetilistat-treated groups (5.3-7.6%) and placebo (7.6%). Adverse events were generally mild to moderate in intensity, occurred on only one occasion and were mostly GI in nature. The incidence of GI adverse events was increased in the cetilistat-treated groups compared to placebo. However, those GI adverse events, such as flatus with discharge and oily spotting, only occurred in 1.8-2.8% of subjects in the cetilistat-treated groups.
Conclusions: Cetilistat produced a clinically and statistically significant weight loss in obese patients in this short-term 12-week study. This was accompanied by significant improvements in other obesity-related parameters. Cetilistat treatment was well tolerated. The risk-benefit demonstrated in this study in terms of weight loss vs intolerable GI adverse effects shows that cetilistat merits further evaluation for the pharmacotherapy of obesity and related disorders.

Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats

Cetilistat is a novel inhibitor of pancreatic lipase. The aim of this report is to evaluate the anti-obesity action of cetilistat in diet-induced obesity (DIO) rats. Cetilistat inhibited rat and human pancreatic lipase activity with an IC (50) of 54.8 nmol/l, and 5.95 nmol/l, respectively, meaning that it is 9.2 times more potent for human pancreatic lipase than for that of rat. Cetilistat was orally administered simultaneously with fat emulsion to Sprague-Dawley rats. Plasma triglyceride (TG) concentrations were measured before and after oral fat loading. The elevation in plasma triglyceride concentration by oral fat loading was reduced by cetilistat in a dose-dependent manner at 3, 10, 30, and 100 mg/kg, indicating that cetilistat reduces intestinal fat absorption in rats. Cetilistat was administered to DIO F344 rats as food admixture in a high-fat diet at 4.9, 14.9, or 50.7 mg/kg/day for three weeks. Both triglyceride and nonesterified fatty acid content in the feces were dose-dependently and drastically increased, suggesting the intestinal breakdown of fat and excretion. Body weight (BW) gain and white adipose tissue (WAT) weight were reduced in a dose-dependent manner. In addition, leptin, TG, and total cholesterol (TC) in plasma were reduced and there were no reports of oily stools. These results suggest that cetilistat ameliorates obesity and hyperlipidemia in DIO rats, a plausible animal model of the most common type of human obesity.

Cetilistat for the treatment of obesity

Obesity is a modern plague in industrialized and developing countries, and currently overweight and obesity cause more deaths worldwide than underweight. Cetilistat is a novel, orally active, gastrointestinal and pancreatic lipase inhibitor. In in vitro studies cetilistat inhibited human pancreatic lipase with an IC50 in the low nanomolar range. In phase II clinical tials in obese patients and in obese patients with type 2 diabetes, cetilistat administered for 12 weeks significantly reduced body weight, serum low-density lipoprotein (LDL) cholesterol and total cholesterol in comparison to placebo. The proportion of obese patients reaching a reduction in baseline body weight of at least 5% was greater in all active arms in comparison to placebo. In obese diabetic patients the levels of glycosylated hemoglobin (HbA1c) were also significatively reduced. Cetilistat showed mild to moderate adverse events, predominantly of gastrointestinal nature (steatorrhea), with an incidence lower than orlistat. It was recently approved in Japan for the treatment of obesity with complications.

Overview of new antiobesity drugs

A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as antiobesity drugs (cetilistat, naltrexone/bupropion combination, liraglutide) is presented. All these drugs produce significant weight loss accompanied by reductions in cardiometabolic health risks. Although the adverse events were rather rare and tended to decrease with the duration of treatment with most of these medications, the drug-specific safety concerns should be seriously considered. In order to ensure an appropriate, efficient and safe implementation of novel antiobesity drugs into the comprehensive treatment of obesity, it will be necessary to establish a network of physicians and other health-care providers well educated in obesity management.