Cholesteryl ester transfer protein inhibition by PD 140195

Area of Science:

• Pharmacology
• Biochemistry
• Cardiovascular Research

Background:

• Cholesteryl ester transfer protein (CETP) activity is linked to atherogenesis.
• Inhibiting CETP may improve lipoprotein profiles and reduce cardiovascular disease.
• Novel therapeutic strategies targeting CETP are of significant interest.

Purpose of the Study:

• To describe a novel CETP inhibitor, 4-phenyl-5-tridecyl-4H-1,2,4-triazole-3-thiol (PD 140195).
• To evaluate the in vitro and in vivo efficacy of PD 140195 as a CETP inhibitor.
• To elucidate the mechanism of inhibition and factors affecting its activity.

Main Methods:

• In vitro CETP inhibition assays using PD 140195 and monoclonal antibody TP2.
• Kinetic studies with fluorescent cholesteryl ester analogs.
• In vivo intravenous infusion studies in anesthetized rabbits.
• In vitro reconstitution studies with bovine serum albumin.

Main Results:

• PD 140195 demonstrated concentration-dependent inhibition of CETP in vitro.
• Molecular modeling suggested PD 140195 mimics cholesteryl ester structure but inhibition was non-competitive.
• PD 140195 selectively inhibited cholesteryl ester transfer, unlike Mab TP2.
• In vivo studies showed only transient CETP inhibition in rabbits.
• PD 140195 activity was significantly reduced in whole plasma, likely due to protein binding.

Conclusions:

• PD 140195 is a novel, non-competitive CETP inhibitor with selective cholesteryl ester transfer inhibition in vitro.
• Its therapeutic potential in vivo is limited by reduced activity in plasma, attributed to binding with other plasma proteins.
• Further research is needed to overcome pharmacokinetic limitations for potential therapeutic applications.