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Inhibitors of acyl CoA:cholesterol acyltransferase
1Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
Journal of Medicinal Chemistry
|April 12, 1996
Summary
Researchers discovered potent inhibitors for acyl CoA:cholesterol acyltransferase (ACAT) by restricting the conformation of acyclic compounds. The most effective inhibitor, compound 4a, showed significant ACAT inhibition in vitro and in vivo.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Pharmacology
Background:
- Acyl CoA:cholesterol acyltransferase (ACAT) plays a crucial role in cellular cholesterol homeostasis.
- Inhibiting ACAT is a therapeutic strategy for managing hypercholesterolemia and related conditions.
- Acyclic (diphenylethyl)diphenylacetamides were previously identified as potential ACAT inhibitors.
Purpose of the Study:
- To explore the impact of conformational restriction on the potency of (diphenylethyl)diphenylacetamide ACAT inhibitors.
- To identify novel and more potent ACAT inhibitors through structural modification.
- To evaluate the in vitro and in vivo efficacy of newly discovered ACAT inhibitors.
Main Methods:
- Synthesis and conformational restriction of acyclic (diphenylethyl)diphenylacetamides.
- In vitro enzymatic assays using rat hepatic microsomes to measure ACAT inhibition (IC50).
- In vivo studies in cholesterol-fed hamsters to assess efficacy (ED50).
Main Results:
- Conformational restriction led to the discovery of several potent ACAT inhibitors.
- cis-[2-(4-Hydroxyphenyl)-1-indanyl]diphenylacetamide (4a) emerged as the most potent inhibitor identified.
- Compound 4a demonstrated an IC50 of 0.04 microM in vitro and an ED50 of 0.72 mg/kg/day in vivo.
Conclusions:
- Conformational restriction is an effective strategy for enhancing ACAT inhibitor potency.
- Compound 4a represents a highly potent ACAT inhibitor with potential therapeutic applications.
- Further development of conformationally restricted ACAT inhibitors is warranted.