Cetilistat

Description

Cetilistat (also known as ATL-962) was approved in September 2013 by the Japanese Ministry of Health, Labor and Welfare for the treatment of obesity, limited to patients with both type 2 diabetes mellitus (T2DM) and dyslipidemia, and with a body mass index (BMI)25 kg/m² in spite of dietary treatment and/or exercise therapy. As with orlistat, cetilistat works via inhibition of pancreatic lipases in the gut to inhibit fat absorption and thereby reduce caloric uptake from diet. The medicinal chemistry program has not been described in the scientific literature, but the patent describing cetilistat also describes the synthesis of analogs with varied aryl substituents and lipophilic tails. The synthesis of cetilistat involves condensation of a hexadecylcarbonochloridate with 2-amino-5-methylbenzoic acid; other analogs were synthesized by varying the carbonochloridate and 2-aminobenzoic acid components. Cetilistat is a potent inhibitor of human and rat pancreatic lipase with IC_50s of 15 and 136 nM, respectively, with little inhibition of trypsin or chymotrypsin.

Chemical properties

Off-white Cryst

Originator

Alizyme PLC (United Kingdom)

The Uses of Cetilistat

Cetilistat is a novel pancreatic lipase inhibitor for the treatment of obesity in both diabetic and non-diabetic patients.

Definition

ChEBI: Cetilistat is a benzoxazine.

brand name

Oblean

Mechanism of action

Cetilistat is a lipase inhibitor. It works in the stomach and small intestine by blocking the absorption of fat from food by blocking enzymes responsible for the breakdown of fat.

Mechanism of action

Orlistat and cetilistat are both gastrointestinal lipase inhibitors. They effectively inhibit the hydrolysis of dietary fat into fatty acids and monoglyceride in the gastrointestinal tract.52 Orlistat is reported to be able to reduce weight while improving lipid distribution, blood glucose, and blood pressure[1]. Specifically, it isdrugs blocking fat absorption.

Side Effects

It has six common gastrointestinal adverse reactions: oily spotting, flatus with discharge, fecal urgency, fatty/oily stools, oily evacuations, and increased defecation. In addition, the content of fat-soluble vitamins A, D, E, and K1 decreases significantly after taking orlistat. Therefore, appropriate supplementation is required[1].

Synthesis

Commercially available hexadecanol (21) was treated with phosgene in THF/toluene to give the corresponding chloroformate (22), which was immediately subjected to commercial 2-amino-5- methylbenzoic acid (23) in pyridine. Subsequent slow addition of methyl chloroformate at room temperature resulted in the formation of cetilistat (IV), which was produced in 31% overall yield from hexadecanol.

Side Effects

Fat in stool , Abdominal cramp, Flatus with discharge, Oily spotting, Bowel incontinence, Flatulence, Abdominal pain, Diarrhea, Soft stools

Precautions

Although Cetislim (Cetilistat) can help overweight patients lose weight and therefore reduce the risk of diabetes or other serious conditions associated with obesity, you will also be advised by your physician to eat a low calorie diet and to exercise regularly.

References

[1] Tong Y, et al. Obesity and insulin resistance: Pathophysiology and treatment. Drug Discovery Today, 2022; 27: 822-830.