Cetilistat Chemical Properties

Melting point:

72.0 to 76.0 °C

Boiling point:

509.7±43.0 °C(Predicted)

Density 

1.02

storage temp. 

2-8°C

solubility 

Chloroform (Slightly), Ethyl Acetate (Slightly)

form 

Solid

pka

2.96±0.20(Predicted)

color 

White to Off-White

InChI

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

InChIKey

MVCQKIKWYUURMU-UHFFFAOYSA-N

SMILES

N1C2=CC=C(C)C=C2C(=O)OC=1OCCCCCCCCCCCCCCCC

CAS DataBase Reference

282526-98-1(CAS DataBase Reference)

Safety Information

HS Code 

2934.99.4400

Cetilistat Usage And Synthesis

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)

Uses

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

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].

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.

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.

References

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

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