Discovery of 1-(4-Fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235):  A Designed, Potent, Orally Active Inhibitor of Cholesterol Absorption

Abstract

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Cholesterol: from feeding to gene regulation

“…There are a lot of dietary, pharmacologic, biliary, cellular and luminal factors capable of influencing intestinal cholesterol absorption. For example the increase of cholesterol intake by diet does not change intestinal cholesterol absorption, while the increase of fiber, plant sterols, fish oil or ezetimibe by diet reduces intestinal cholesterol absorption [17, 50,82,91,97,108,119]. Among the proteins indicated as intestinal cholesterol transporters, it has been recently demonstrated that NPC1L1 (Nieman-Pick C1-like protein1), that is expressed predominantly in the gastrointestinal tract with peak expression in the proximal jejunum, is the most involved.…”

Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS-deficient ApoE ko mice

“…Ezetimibe inhibits cholesterol uptake as well as its reuptake from the enterohepatic cycle in the mucosa of the small intestine, where its direct molecular target was recently identified as the Niemann-Pick-C1-Like1 (NPC1L1) protein 22,23 . Results from preclinical and clinical studies have demonstrated that Ezetimibe potently lowers plasma cholesterol and favourably modulates lipoprotein profiles [24][25][26] . In a previous study, Ezetimibe prevented atherosclerosis development in apoE ko mice when the drug was given early on with a high fat "western" diet (WD), a low fat diet, or a cholesterol free diet 27 .…”

Deficiency of Niemann-Pick C1 Like 1 Prevents Atherosclerosis in ApoE −/− Mice

“…Ezetimibe, a potent cholesterol absorption inhibitor, has been shown to lower plasma cholesterol by selectively inhibiting dietary and biliary cholesterol uptake at the brush border of the small intestine, inferring that ezetimibe could be interacting with an intestinal cholesterol transporter. [1][2][3] The understanding of the molecular mechanism by which intestinal cholesterol absorption occurs has recently been elucidated. 4 The protein, Niemann-Pick C1 Like 1 (NPC1L1), was identified and found to be highly expressed in the proximal intestine and localized to the surface of enterocytes.…”