Sunday, January 31, 2016

Cetilistat | Inhibitor of Gastrointestinal Lipases | Inhibitor of Pancreatic Lipases | Anti-Obesity Drug

Cetilistat [2-(Hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one] is a novel highly lipophilic benzoxazinone that inhibits gastrointestinal (GI) and pancreatic lipases, and is chemically distinct from Orlistat [1].

Cetilistat: 2D and 3D Structure

Pancreatic lipase is the enzyme that breaks down triglycerides in the intestine. Inhibition of this enzyme ensures that triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.
In Phase I clinical trials in healthy volunteers, Cetilistat increased faecal fat excretion and was well tolerated. 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.
The NDA submission is based on the results of three Phase 3 clinical trials in obese patients with type 2 diabetes and dyslipidemia: a 52-week placebo-controlled, double-blind study to evaluate the efficacy and safety, and two open-label studies to evaluate safety, 24-week and 52-week respectively. The results of the 52-week placebo-controlled, double-blind study demonstrate that Cetilistat 120mg three times daily is superior to placebo in the primary endpoint, with a mean reduction in body weight from baseline of -2.776% with Cetilistat versus -1.103% with placebo (p=0.0020). Greater reduction in HbA1c and low-density lipoprotein cholesterol were also observed in patients treated with Cetilistat, compared to placebo. In all these three studies, Cetilistat showed a good safety profile and was well tolerated.
Cetilistat was approved in Japan in September 2013 for the treatment of obesity. Cetilistat (Tradename: Oblean) is approved for a dosage of 120 mg three times a day for the treatment of obesity with complications.
The drug was discovered by UK based Alizyme PLC and in 2003 Takeda acquired the rights for development and commercialisation for Japan. Norgine acquired all rights to the product from Alizyme in October 2009 [3].

Cetilistat Synthesis

US20030027821A1: It appears to be the industrial process. The yields are in the range of 30-35%.

1H NMR (Estimated) for Cetilistat

Experimental: 1H-NMR δH (400 MHz, CDCl3) 0.87 (3H, t, J 6.8, CH2CH3), 1.24-1.45 (26H, m, 13×CH2), 1.75-1.83 (2H, m, OCH2CH2), 2.41 (3H, s, ArCH3), 4.41 (2H, t, J 6.7, OCH2), 7.3 (1H, d, J 8.3, ArH), 7.51 (1H, dd, J 8.5, 2.0, ArH), 7.90 (1H, d, J 1.1, ArH); m/z (ES+) 402 (MH+); M Pt. 72-73° C.

Sideeffects: The most frequently experienced adverse events were those involving the gastrointestinal (GI) tract. The proportion of patients and the total number of GI adverse events reported in each of the active treatment groups were higher compared to the placebo group. However, GI adverse events were predominantly mild to moderate in intensity, with no evidence of a dose relationship.
The most frequently reported GI-related adverse events included increased defecation, soft stools, abdominal pain, flatulence and fatty/oily stool, which were all reported more frequently in the treatment arms compared to the placebo arm.
Faecal incontinence, flatus with discharge, oily evacuation and oily spotting occurred in only 1.8-2.8% of subjects in the active treatment arms and was not dose-related. Adverse events generally occurred on only one occasion and resolved rapidly.
Serum vitamin D, vitamin E and β-carotene levels were decreased significantly in the Cetilistat treatment arms. Generally, these reductions in vitamin levels did not take the levels outside the normal range and none required the use of vitamin supplements.

1. Kopelman, P.; et. al.  Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes (Lond) 2007, 31(3), 494-499.
2. Hodson, H.; et. al. 2-Oxy-benzoxazinone derivatives for the treatment of obesity. US20030027821A1
3. Cetilistat Approval (here).