SCH-48461

SCH-48461 is a cholesterol absorption inhibitor that was developed by Schering-Plough. It is a potent and selective inhibitor of the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is a critical mediator of cholesterol absorption in the intestine. SCH-48461 has been shown to reduce cholesterol absorption in both animals and humans, and it has potential therapeutic applications in the treatment of hypercholesterolemia and related conditions.

Mechanism of Action

SCH-48461 inhibits cholesterol absorption by binding to the NPC1L1 protein in the enterocytes of the small intestine. This prevents the uptake of dietary and biliary cholesterol into the body, thereby reducing the amount of cholesterol that is available for incorporation into lipoprotein particles and secretion into the bloodstream.

Pharmacology

In preclinical studies, SCH-48461 has been shown to have a high degree of selectivity for the NPC1L1 protein, with minimal off-target effects. It is orally active and has a long duration of action, which makes it suitable for once-daily dosing. In human studies, SCH-48461 has been shown to reduce cholesterol absorption by approximately 50%, with a corresponding decrease in plasma cholesterol levels.

Clinical Development

SCH-48461 has undergone Phase I and II clinical trials for the treatment of hypercholesterolemia. In these trials, it was generally well tolerated and showed a significant cholesterol-lowering effect. However, further development of SCH-48461 was discontinued for undisclosed reasons.

See Also

• Ezetimibe, another cholesterol absorption inhibitor that is currently marketed for the treatment of hypercholesterolemia.
• Niemann-Pick disease, a genetic disorder that is caused by mutations in the NPC1 and NPC2 genes.

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  SCH-48461