Cholesterol absorption inhibitor

The cis P-lactams 57 are shown to act as cholesterol absorption inhibitors <96BMCL1947> and 58, an analogue of the dipeptide Phe-Gly methyl ester, is a protease inhibitor <96BMCL983>. A straightforward synthesis of proclavaminic acid 59, a biosynthetic precursor of clavulanic acid, is reported <96TA2277>. 

Ezetimibe is the first drug in a new class of agents referred to as cholesterol absorption inhibitors. Ezetimibe blocks biliary and dietary cholesterol as well as phytosterol (plant sterol)... 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

Zaks, A. and Dodds, D.R., Enzymatic glucuronidation of a novel cholesterol absorption inhibitor, Sch 58235. Appl. Biochem. Biotechnol., 1998, 73, 205. 

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

Fig. 7.n Synthetic strategies to overcome benzylic hydroxylation in a series of cholesterol absorption inhibitors. Positions of metabolism are marked with an asterisk. 

Fig. 7.15 Structures of cholesterol absorption inhibitors SCH 48461 (A) and SCH 58235 (B). Metabolism of SCH 48461 occurs by aromatic hydrox-ylation (1) benzylic hydroxylation (2) and O-demethylation (3, 4). Metabolism is blocked in SCH 58235 at 1 and 4 or results in increases in potency at 2 and 3.

Ezetimibe (1) is the first in a new class of cholesterol absorption inhibitors that reduce plasma LDL-C levels by direct inhibition of the uptake of free cholesterol from the... 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

Kambara T, Tomioka K (1999) J Org Chem 64 9282 For their evaluation as cholesterol absorption inhibitors, see... 

Keywords Biological activity Cholesterol absorption inhibitors Ketene-imine cycloaddition Spiroazetidin-2-ones Spiro-(3-lactams Synthetic intermediates (3-Lactamase inhibitors... 

Burnett et al. [16] have reported monocyclic (3-lactam I as a potent cholesterol absorption inhibitor in vivo, and this can inhibit the absorption of dietary... 

Scheme 24 Enantioselective synthetic route to cholesterol absorption inhibitor spiro-P-lactams...

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

CAIBP Cholesterol absorption inhibitor binding protein... 

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

Reyderman L, Kosoglou T, Statkevich P, Pember L, Boutros T, Maxwell SE, Affrime M, Batra V. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. International J Clin Pharmacol Ther 2004 42(9) 512-8. 

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