“…Recent clinical trials and extensive epidemiological studies support the reduction of low-density plasma lipoproteins (LDL) as a major goal in the treatment and prevention of coronary heart disease (CHD) and with cholesterol absorption inhibitors (CAIs; e.g., Tiqueside ( 6 , CP 88,818; Pfizer), 2 (SCH 48461; Schering-Plough)) (Figure ). Even with the current diverse repertoire of therapeutic agents and combinations thereof, a significant portion of the hypercholesterolemic population is unable to reach target serum cholesterol levels, or drug interaction and safety issues preclude the prolonged treatment regimen needed to reduce CHD risk …”
(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.
“…Recent clinical trials and extensive epidemiological studies support the reduction of low-density plasma lipoproteins (LDL) as a major goal in the treatment and prevention of coronary heart disease (CHD) and with cholesterol absorption inhibitors (CAIs; e.g., Tiqueside ( 6 , CP 88,818; Pfizer), 2 (SCH 48461; Schering-Plough)) (Figure ). Even with the current diverse repertoire of therapeutic agents and combinations thereof, a significant portion of the hypercholesterolemic population is unable to reach target serum cholesterol levels, or drug interaction and safety issues preclude the prolonged treatment regimen needed to reduce CHD risk …”
(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.
“…As a class, these compounds were attractive because they had extremely low systemic exposure and were assumed to be lumenally active but lacked robust in vivo activity. One of these compounds, tiqueside ( 1, CP-88,818), had progressed through phase II clinical trials where it demonstrated adequate efficacy but inadequate potency (4 g/day was required to achieve >20% reduction of LDL cholesterol). …”
We have explored the use of steroidal glycosides as cholesterol absorption inhibitors which act through an unknown mechanism. The lead for this program was tigogenin cellobioside (1, tiqueside) which is a weak inhibitor (ED50 = 60 mg/kg) as measured in an acute hamster cholesterol absorption assay. Modification of the steroid portion of the molecule led to the discovery of 11-ketotigogenin cellobioside (5, pamaqueside) which has an ED50 of 2 mg/kg. Replacement of the cellobiose with other sugars failed to provide more potent analogs. However, large improvements in potency were realized through modification of the hydroxyl groups on the cellobiose. This strategy ultimately led to the 4", 6"-bis[(2-fluorophenyl)carbamoyl]-beta-D-cellobiosyl derivative of 11-ketotigogenin (51) with an ED50 of 0.025 mg/kg in the hamster assay, as well as the corresponding hecogenin analog 64 (ED50 = 0.07 mg/kg).
“…8 In humans dosed 4 g/day for 12 weeks, 2 was welltolerated and lowered LDL cholesterol levels by more than 20%. 9 These effects were associated with a decrease in fractional cholesterol absorption and increased excretion of fecal neutral sterols. The bioavailability of 2 in dogs was low (1.7%), but not insignificant.…”
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