Ezetimibe development

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

C4 promoted the preinstallation of these metabolically productive functionalities. Coupling the above observations, it became clear to us to simultaneously optimize all regions of the structure and target what is now known as ezetimibe (1) (Rosenblum et al., 1998). As the S AR was developed with an in vivo assay, improvement in activity reflected a complex balance between intrinsic receptor affinity and ADME considerations. We now appreciate that the site of action is the enterocyte on the intestinal villi, and thus systemic absorption is not required for activity. The above outlined combination of synthetic organic... 

A 50-year-old woman with previous autoimmune thyroid disease taking atorvastatin developed acute hepatitis when she also was given ezetimibe (4). Further investigations, including liver biopsy, showed a probable drug-induced autoimmune hepatitis. 

Animal tests can be extremely elaborate. Ezetimibe (Zetia, 2.25), a cholesterollowering drug, was developed in the mid-1990s through testing in rats (Figure 2.9). The mode of action was known to be inhibition of active transport of cholesterol in the small intestine, but the exact mechanism of transport was unknown. Without an established mode of action, a... 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

The most notable discovery in the area of monocyclic azetidin-2-ones is its development as cholesterol absorption inhibitors. The monocyclic azetidin-2-one 559, earlier known as SCH58235, was discovered to have potential cholesterol absorption inhibition property in the late 1990s <1998JME973>. This compound is now in clinical application with the name ezetimibe to treat hypercholesterolemia <2004JME1>. It has been observed recently that the new nonhydrolyzable glycoside 560, prepared using the scaffold of ezetimibe, is also a potent inhibitor of cholesterol absorption <2004AGE4653>. 

As far as research collaboration is concerned, the Schering-Plough manufacturing process for its cholesterol absorption inhibitor, Ezetimibe (Zetia), exemplifies the collaboration case. The close interaction between Research and Development, aided by the delay caused by the realization that the first API structure (XVI) had to be modified to overcome metabolism issues, provided the intellectual resource and the time for a fuller understanding of the chemistry needed to create the chiral (3-lactam ring. 

Nor are the contributions to be made by p-lactam structures to the pharmaceuticals field over. The extraordinary developments of recent years in cholesterol absorption inhibitors (CAIs) based on the p-lactam ring deserve some mention, especially since Dr. T. K. Thiruvengadam in our chemical process development organization in Schering-Plough is the brilliant architect of one of the patented syntheses of this novel class of CAIs. His synthesis35 of Ezetimibe (Zetia), outlined in Scheme 13, serves to (a) introduce this new direction in the development of novel p-lactam medicinals and (b) end this excursion in the field of p-lactams. 

EZETIMIBE LIPID-LOWERING DRUGS Risk of gallstones with fibrates Uncertain Stop co-administration if symptoms develop... 

In a recent publication, Briining et al. [12] developed ezetimibe anhy-drate from the monohydrate form by drying at 393 K for 1 day in an oven. This anhydrate form was then characterized using X-ray diffraction with 2 = 1.5406 A and Cu Kq, as the radiation source. Scanning was done at 26 = 3-69.99°. It was found that the anhydrate structure analyzed in this research is quite similar to the monohydrate structure, with the exception that due to fewer donor and acceptor atoms, a different conformation of the propyl group and a different hydrogen-bond pattern occurred. 

There are few spectrophotometric methods published to determine ezetimibe in pharmaceutical dosage forms. The first one was established by Mishra et al. [17] by applying colorimetric assay of phenol group. This method was developed based on the reaction between Folin-Ciocalteu s (FC) phenol reagent and phenol group of ezetimibe, which results in a blue chromogen that was then observed at 760 nm. 

Another spectrophotometric method used the derivative method. Rajput and Raj [19] developed a first-order derivative zero-crossing method to analyze ezetimibe in combination with simvastatin. This method was further applied to determine ezetimibe in combination with lovastatin. The first derivation method also applied to determine ezetimibe in combination with rosuvastatin [20]. Besides the first-derivative method, second- and third-derivative methods were also reported for defermining ezetimibe as a single compound in its dosage form [21]. Flowever, the third-derivative method yielded the lowest limits of defecfion and quantitation relative to other methods used in this research. The maximum wavelength also remained constant regardless of fhe derivative method applied. 

In more recent development, chemometric or multivariate calibration techniques have been applied into spectrophotometric methods. As reported by Palabiyik and Onur [24], principal component regression and partial least square were used to determine ezetimibe in combination with simvastatin. This method offers advanfages such as no chemical prefreafmenf prior to analysis as well as no need to observe graphical spectra and calculations as with the derivative method. In addition, the instrumentation used is also simpler. 

The simplest UV-spectrophotometric method was developed by Rajesh and Reddy [25] to determine ezetimibe as a single compoimd. This method was based only on an absorbance measurement of ezetimibe af one wavelength. Similarly, Jain et al. [26] also employed a simple method to determine ezetimibe in combination with simvastatin. In this method, ezetimibe was observed at a wavelength where simvastatin did not give interference. While no LOD and LOQ values were reported, the linearity of the method was over the range of 5-20 pg/mL. 

For the purpose of analyzing ezetimibe in combination with simvastatin, three HPTLC methods have been developed. The first method was developed by Shivshankar et al. [33] and yielded higher Rf values for either ezetimibe or simvastatin. In the method developed by Dhaneshwar et al. [30], a combination of toluene and isopropanol was shown to produce shorter Rf times for ezetimibe and simvastatin, leading to methods of shorter duration and lower mobile phase consumption. The recent method developed by Dixit et al. [31] used combination of acetone and n-hexane as the mobile phase and resulted in shorter Rf values when compared to the other two methods for assessing ezetimibe in combination with simvastatin. This method has also been validated to distinguish the degradation products of ezetimibe. Further, during the determination of ezetimibe in combination with atorvastatin, shorter Rf values were obtained as well as better peak shape when a combination of toluene and methanol was used as the mobile phase [30]. 

The first liquid chromatography method introduced to determine ezetimibe and its metabolites was developed by Ezzet et al. [58], and the method was used to model the pharmacokinetics of ezetimibe in humans. The liquid chromatography-mass spectrometry (LC-MS) method was used to determine imchanged ezetimibe and total ezetimibe (imchanged ezetimibe together with ezetimibe glucoronide) in human plasma samples. 

More recent publications [50,61-65] reported the development and validation of LC methods for the analysis of ezetimibe and its metabolites in biological samples. Most of the extraction methods used liquid extraction with ferf-butyl methyl ether as the extracting solvent, since this solvent gave higher efficiency of recovery of ezetimibe as compared to other organic solvents [50]. In this analysis method, attention was given to the sample stability before and during analysis, and it was reported that... 

In a randomised, erossover study 32 otherwise healthy subjects with hy-pereholesterolaemia were given either ezetimibe 10 mg daily, fluvastatin 20 mg daily or both drugs in combination for 14 days. The combination was well tolerated, no significant pharmacokinetic interaction occurred, and an enhanced lowering of LDL-cholesterol was noted, which was considered to be clinically favourable. However, a case report describes a 52-year-old man taking fluvastatin 80 mg daily who developed elevated creatinine kinase levels 8 weeks after ezetimibe 10 mg daily was added. 

A case report describes a 48-year-old man taking ezetimibe 10 mg daily, and rosuvastatin 5 mg on alternate days, who developed rhabdomyolysis within 3 weeks of starting to drink 200 mL of pomegranate juice twice weekly. Although the patient had been stable taking ezetimibe with rosuvastatin for 15 months he had a history of myopathy with statins and had an elevated creatine kinase before statin treatment had started. ... 

Bandyopadhyay, S., Katare, O.P., Singh, B., 2014. Development of optimized supersaturable setf-nanoemulsifying systems of ezetimibe effect of polymers and efflux transporters. Expert Opin. Drug Deliv. 11, 479—492. 

Dietary cholesterol is absorbed by intestinal ABC cholesterol transporter (Chapter 41). Once inside the cell, cholesterol is esterified by acyl CoA-cholesterol-acyl transferase (ACAT) to form the hydro-phobic cholesteryl ester. This reaction facilitates and maximises absorption of cholesterol, which is probably an advantage to people deprived of cholesterol-rich food such as meat. Unfortunately, efficient absorption of cholesterol is not an advantage to the affluent. However, margarines enriched with plant sterols have been used to inhibit cholesterol absorption in an attempt to lower blood cholesterol. Research is under way to develop ACAT inhibitors that potentially are cholesterol-lowering drugs. Ezetimibe is a new drug that inhibits cholesterol absorption by inhibition of the intestinal cholesterol-transporter protein NPCILI (Niemann-Pick Cl-like protein 1). 

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