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].
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| 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%.
Identification:
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| 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.
References:
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).
