Pancreatic lipase inhibitor orlistat

Enantioselective hydrogenation of />-kelo esters catalyzed by the modified Raney Ni is useful for the synthesis of biologically active compounds, as shown in Figure 32.15 [56-58]. A large-scale synthesis of (-)-tetrahydroHpstatin (orlistat), a pancreatic lipase inhibitor (F. Hoffmann-La Roche AG), is carried out using this method [58]. 

The active ingredient of Xenical, orlistat, is a pancreatic lipase inhibitor. Side-effects include faecal urgency, liquid oily stools and flatulence. Xenical capsules are administered before, during or up to 1 hour after the two main meals, twice daily. 

Orlistat is a pancreatic lipase inhibitor used in conjunction with a hypocaloric diet to reduce the absorption of dietary fat in obese patients. Orlistat is administered twice daily immediately before, during or up to 1 hour after each meal. If the meal contains no fat there is no need to take Orlistat. 

Orlistat (Xenical /Roche) is a reversible gastric and pancreatic lipase inhibitor. The compound has no effect on appetite suppression but rather acts by inhibiting dietary fat absorption from the GI tract. Sibutramine (Meridia /Abbott) and its major active metabolites are re-uptake... 

Orlistat, a semisynthetic derivative of lipstatin, is a potent and selective inhibitor of pancreatic lipases. It was designed to treat obesity. Orlistat prevents approximately 25% of dietary fat from being absorbed. Very little of the drug itself is absorbed. Its adverse effects are therefore restricted to those related to fat malabsorption, with potential losses of fat-soluble vitamins. It has a relatively small effect on body mass, but enough to realise in one study a 37% reduction in the incidence of type 2 diabetes. 

In 1987, scientists at Hoffmann-La Roche described their discovery of hpstatin (5), a secondary metabolite isolated from Strptomyces toxytricini, and demonstrated that it is a potent inhibitor of pancreatic lipase.Simple hydrogenation of 5 formed terahydrolipstatin (1,USAN, orlistat) which possesses comparable biological activity but is more stable than 5. Orlistat (1, Xenical ) works through pancreatic lipase inhibition. Pancreatic lipase is the key enzyme of dietary triglyceride absorption, exerting its activity... 

Regrettably, the pharmacologist must confess that no drugs exist that can be recommended for the purpose of weight reduction. The so-called appetite suppressants (anorexiants) act only, if at all, for a limited period and are fraught with side effects. Most anorexiants are derivatives of metham-phetamine that have been withdrawn from the market. A different mechanism of action is involved in the case of an inhibitor of pancreatic lipase, which is required in the intestines for fat absorption. This inhibitor (orlistat) diminishes fat absorption so that fats reach the lower bowel, where they can cause disturbances flatulence, steatorrhea, and frequent need to relieve the bowels occur in about 30% of affected subjects. These symptoms correspond exactly to those seen in pancreatic hypofunction which are then usually treated with pancreatic lipase. Before an obese person submits to treatment with orlistat, he or she should voluntarily reduce the food fat content by one half to live free of such unpleasant adverse effects. 

Orlistat (32 tetrahydrolipstatin, Xenical ) is a potent inhibitor of pancreatic lipase [23] which has been launched for the treatment of obesity in 1998. Large amounts of 32 required for clinical development were obtained using a route based on the enantioselective reduction of P-ketoester 29 to provide P-hydroxyester R)-30 followed by diastereoselective elaboration strategies (via (S,S,i )-31, Scheme 6)... 

Orlistat (tetrahydrolipstatin) is a reversible inhibitor of oral, gastric, and pancreatic lipases. This inhibitor forms an ester linkage with serine (serine-152) in the active site of the lipase so that a decrease in the rate of lipid hydrolysis will occur [37]. Orlistat decreases the oral taste sensitivity to both oleic acid and triolein in obese subjects [38]. These results further suggest a role for lingual lipase in oral fat hydrolysis and detection. However, a conclusive role for human lingual lipase in oral fatty acid hydrolysis and detection still remains imclear at the present time [39]. 

Orlistat (Fig. 20.7) is the only Gl tract dmg indicated in the BNF, and is a lipase inhibitor, which reduces fat intake. This dmg is a synthetic analogue of lipstatin which is a namrally occurring substance produced by Streptomy-ces toxytricini. Orlistat is an iueversible inhibitor of pancreatic and gastric lipases and as such it prevents these lipases from breaking down triglycerides into their absorbable form (free fatty acids and monoglycerols). The triglycerides are thus eliminated without absorption and thus there is a decreased dietary intake of fat. 

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