gem-Diphosphonate and gem-phosphonate-phosphate compounds with specific high density lipoprotein inducing activity

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Atherosclerosis is a major cardiovascular disease linked to abnormal lipid profiles.
• High-density lipoproteins (HDL) play a protective role in preventing atherosclerosis.
• Developing agents that increase HDL levels is a therapeutic goal.

Purpose of the Study:

• To synthesize and evaluate novel diphosphonate compounds for their ability to raise plasma HDL and HDL-C levels.
• To identify structure-activity relationships for optimal lipid-altering effects.
• To assess the antiatherosclerotic potential of these compounds.

Main Methods:

• Synthesis of a library of diphosphonate compounds and related derivatives.
• In vivo screening in normal rats to measure plasma lipid levels, specifically HDL and HDL-C.
• Pharmacological evaluation of promising candidates.

Main Results:

• Several novel diphosphonate compounds demonstrated significant induction of plasma HDL and HDL-C.
• Specific structural modifications were correlated with enhanced lipid-altering activity.
• Dimethyl alpha-(dimethoxyphosphinyl)-p-chlorobenzyl phosphate (mifobate) emerged as a highly active compound.

Conclusions:

• New diphosphonate derivatives possess the ability to increase HDL and HDL-C levels.
• Mifobate (SR-202) exhibits significant potential as an antiatherosclerotic agent.
• Further pharmacological and clinical studies of mifobate are warranted.