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`HIGHLIGHTS
`
`FRESH FROM THE PIPELINE
`Ezetimibe
`
`John Earl and Peter Kirkpatrick
`
`Ezetimibe (Zetia), the first in a new class of
`agents that inhibit cholesterol absorption in the
`intestine, was approved by the FDA in October
`2002 for the reduction of cholesterol levels in
`patients with hypercholesterclaemia. What
`impact is it likely to have on the multi-billion(cid:173)
`dollar market for cholesterol-lowering drugs?
`
`Many clinical trials and extensive epidemiolog(cid:173)
`ical studies have clearly established the benefits
`of reducing serum levels of low-density
`lipoprotein cholesterol (LDL-C) and total
`cholesterol (TC) on coronary heart disease, a
`leading cause of death and morbidity in the
`developed world'. Although the statin class of
`drugs, which lower LDL-C and TC by inhibit(cid:173)
`ing cholesterol biosynthesis, have proved
`highly effective in general, many patients
`taking statins continue to have higher-than(cid:173)
`recomrnended LDL-C and TC
`levels.
`Consequently, several approaches have been
`pursued to develop novel cholesterol-lowering
`drugs, with one such program leading to the
`discovery and development of the small(cid:173)
`molecule drug ezetimibe (Zetia; Schering
`Plough/Merck).
`
`Therapeutic hypothesis
`Scrum cholesterol is primarily regulated by
`two organs: the liver, which produces cholesterol
`for use in digestion, and the intestine, which
`absorbs cholesterol from food and from bile.
`
`Stalins inhibit cholesterol biosynthesis in the
`liver, and so agents that inhibit cholesterol
`absorption in the intestine might be expected
`to have additive effects when used in combina(cid:173)
`tion with statins.
`Acy! co enzyme A: cholesterol acyltrans(cid:173)
`ferase (ACAT). an enzyme involved in chol(cid:173)
`esterol absorption in the intestine, was
`initially chosen as a target, and a class of
`compounds
`that
`inhibited cholesterol
`absorption in a cholesterol-fed hamster
`model was identified'. However, comparison
`of in vivo potency with in vitro ACAT
`inhibitory activity in structurally related
`compounds showed no correlation, indicat(cid:173)
`ing that these compounds inhibit cholesterol
`absorption by a different mechanism>, which
`is still unknown.
`
`Drug composition
`The original compound series' was based on
`an azetidinone nucleus, which is crucial for
`in vivo activity. Extensive structure-activity
`studies' and rational considerations of meta(cid:173)
`bolic properties'~ led to the discovery of SCH
`58235, subsequently named ezetimibe (FIG. I),
`which showed high efficacy as an inhibitor of
`cholesterol absorption in the cholesterol-fed
`hamster model' and a range of other choles(cid:173)
`terol-fed animal models of human cholesterol
`metabolism•, and which was thus chosen as
`the clinical development candidate.
`
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`.:,:,'~:':·~;,r·~,·:;.,i:\ti•i~~i::;:
`
`Figure 1 I Structure of ezetlmlbe. Structure-activity studies around the 2·azetidinone core showed that
`the key elements for the inhibition of cholesterol absorption are an N-1-aryl group. a 4S-alkoxyaryl
`substituent and a C-3 arylalkyl substituent'-'; these studies led to the compound SCH 48461. Further
`structurEractivity studies that considered putative metabolites of SCH 48461, with the aim of blocking
`'non-productive' metabolism fintroducing fluorine at potential metabolic sites on the N-1 and C-3 aromatic
`rings) and pre-activating ·productive" metabolism (stereospecific benzyfic hydroxylation of the C-3 side
`chain), resulted in SCH 58235 (ezetimibe), which had a 50-fold increase in in vivo potency over SCH 48461
`in the chotesterol·fed hamster model'-'. A scalable stereoselective synthesis has been reported'.
`
`Trfal data
`In patients with hypercholesterolaemia, eze(cid:173)
`timibe { l 0 mg orally, once-daily) reduces levels
`ofLDL-C, TC, apolipoprotein B (the major
`protein constituent ofLDL) and triglycerides
`(increased levels of which can promote athero(cid:173)
`sclerosis), and increases levels of high-density
`lipoprotein cholesterol (decreased levels of
`which are associated with the development of
`atherosclerosis)•. Maximal responses are typi(cid:173)
`cally reached within two weeks and are main(cid:173)
`tained during chronic therapy. Ezetimibe was
`generally well tolerated, with the overall inci(cid:173)
`dence of adverse events reported with ezetim(cid:173)
`ibe being similar to that reported with placebo.
`In two 12-week studies in 1,719 hypercholes(cid:173)
`terolaemic patients, ezetimibe as a monotherapy
`reduced LDL-C by 18% compared with a I%
`increase with placebo•. Adding ezetimibe to
`ongoing statin therapy in an 8-week study with
`769 hypercholcstcrolaemic patients who had
`not reached
`their National Cholesterol
`Education Program (NCEP) II LDL-C goal
`reduced LDL-C by 25% compared with a 4%
`reduction with addition of placebo, with 72% of
`the patients receiving ezetimibe reaching their
`NCEP II goal compared with 19% of patients
`receivi~g placebo•. Finally, in four 12-week trials ·
`involving 2,382 previously untreated hyper(cid:173)
`cholesterolaemic patients, ezetimibe in combi(cid:173)
`nation with various doses of one of four statins
`(including the most commonly used Stalins,
`atorvastatin and simvastatin) reduced LDL-C
`more than statin alone in each case.
`
`Indications
`Ezetimibe administered alone or in combina(cid:173)
`tion with a statin is indicated as adjunctive
`therapy to diet for the reduction of elevated
`TC. LDL-C and Apo Bin patients with primary
`hypercholesterolaemia.
`In addition, on the basis of small-scale trials,
`ezetimibe is also approved for use in two rare
`genetic disorders. The combination of eze(cid:173)
`timibe and atorvastatin or simvastatin is indi(cid:173)
`cated for the reduction of elevated TC and
`LDL-C levels in patients with homozygous
`familial hypercholesterolaemia as an adjunct to
`other lipid-lowering treatments, and ezetimibe
`is indicated as an adjunctive therapy to diet for
`the reduction of elevated levels of the sterols
`sitosterol and campesterol in patients with
`homozygous sitostcrolaemia.
`II>
`
`NATURE REVIEWS I llRUG DISCOVERY
`
`VOLUME 2 I FEBRUARY 2001 In
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`PENN EX. 2179
`CFAD V. UPENN
`IPR2015-01835