Low Density Lipoprotein Cholesterol Lowering Agents Cholesterol Absorption Inhibitors

Ezetimibe 10 was discovered as part of a program directed at identifying novel ACAT inhibitors for lipid lowering. These azetidinone leads, although weak as ACAT inhibitors, were efficacious in lowering cholesterol in animals, suggesting that they might work by a different mechanism.71-73 This discovery represents a tour de force in lead optimization, driven primarily by increasing in vivo efficacy by minimizing metabolism, and is in sharp contrast to the more common target-directed discovery approaches employed today. The biochemical target for ezetimibe was unknown at the time that discovery efforts began and has only recently been elucidated.74

The separation between ACAT potency and in vivo efficacy was pronounced for azetidinone 28 (Figure 12). It was a relatively weak ACAT inhibitor (IC50 = 2.6 mM), yet when given orally to hamsters at 10mgkg_ 1 day_ 1, lowered serum cholesterol by 28% (ED50 = 2mgkg~1) and also lowered serum cholesteryl ester by 93%. Compound 28 was even more potent in dogs and monkeys. The results suggested that 28 blocked cholesterol absorption near the intestinal wall by an unknown mechanism, with the in vivo efficacy of 28 being attributable to its metabolite, 29. The introduction of a chiral hydroxyl group on the aliphatic side chain improved the in vivo efficacy of 30 (ED50 = 0.9mgkg_ 1) twofold compared with 28. Since metabolic degradation occurred by hydroxylation of the unsubstituted phenyl ring in 30, ^-fluorophenyl groups were introduced at two of the rings to give 31, and the related phenol 10 minimized systemic exposure to localize the compound in the intestines. The resulting compound, ezetimibe 10, displayed excellent in vivo oral efficacy in lowering plasma cholesterol across a variety of animal species, including hamsters (ED50 = 0.04mgkg_ 1), rat (ED50 = 0.03 mgkg" 1), monkey (ED50 = 0.00 05 mgkg" 1), and dog (ED50 = 0.007mgkg_ 1), with minimal systemic exposure. Thus, ezetimibe is more than 50-fold more effective in animals than the original lead, 28.

Ezetimibe 10 has a long half-life, is suitable for once-a-day oral dosing, is rapidly absorbed, and becomes conjugated as its glucoronide metabolite that is excreted in the bile. This mechanism efficiently delivers ezetimibe to its site of action in the intestine, and recycling in the enterohepatic recirculation further insures that a high concentration of drug is maintained in the intestine. In contrast to statins that are preferentially prescribed for evening dosing, ezetimibe can

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