SCH-48461 explained

SCH-48461 is a cholesterol absorption inhibitor.^{[1] [2]}

During the early phases of an NPC1L1 inhibitor discovery program at Schering-Plough, conformationally restricted analogs based on the 2-azetidinone backbone were targeted by Burnett and co-workers.^[3] Early in the biological evaluation, it became apparent that even though the in vitro ACAT inhibitory activity of these analogs was modest (e.g., IC₅₀ values of 2–50 mM), they exhibited significant activity in a cholesterol-fed hamster model (CFH). The discovery of the prototypical 2-azetidinone CAI, SCH-48461 (ACAT IC₅₀ ~26 mM, ED₅₀ of CE reduction in hamsters ~2.2 mpk) and the details of the first-generation SAR have been described in detail.^[4]

Notes and References

1. Salisbury BG, Davis HR, Burrier RE, etal . Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461 . Atherosclerosis . 115 . 1 . 45–63 . May 1995 . 7669087 . 10.1016/0021-9150(94)05499-9.
2. Dujovne CA, Bays H, Davidson MH, etal . Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study . J Clin Pharmacol . 41 . 1 . 70–8 . January 2001 . 11144997 . 10.1177/00912700122009854. 30737100 .
3. 10.1021/jm00038a001 . 2-Azetidinones as Inhibitors of Cholesterol Absorption . Journal of Medicinal Chemistry . 1994 . 37 . 12 . 1733–1736 . Duane A. . Burnett . 8021912.
4. 10.1021/jm960405n . 2-Azetidinone Cholesterol Absorption Inhibitors: Structure−Activity Relationships on the Heterocyclic Nucleus . Journal of Medicinal Chemistry . 1996 . 39 . 19 . 3684–3693 . John W. . Clader . 8809157.