LY-2484595

Description

The “trapib” family of drugs are cholesterylester transfer protein (CETP) inhibitors that increase high-density lipoproteins (HDLs) and decrease low-density lipoproteins (LDLs) in the body. The molecules typically contain aromatic rings, nitrogen heterocycles, and multiple trifluoromethyl groups.
The first CETP inhibitor, torcetrapib, was developed by Pfizer and was discontinued because of adverse cardiac side effects. Two more recent ones, anacetrapib (Merck) and evacetrapib (Lilly), showed more promise, but they too are having tough sledding.
Anacetrapib has been in Phase II and III trials for more than a decade. Of some concern is that it remains in patients’ bodies for as long as 4 years. In 2013, however, Merck launched a 30,000-participant, double-blind, placebo-controlled Phase III study of anacetrapib that will continue through 2017.
Lilly, on the other hand, has?pulled the plug on evacetrapib. It did so in late 2015 after a 12,000-participant study showed that the drug did not reduce cardiovascular events compared with the placebo. The failure caused Lilly to take a $90 million charge against its fourth-quarter earnings.

The Uses of LY-2484595

Evacetrapib is an inhibitor of?cholesteryl ester transfer protein (CETP). CETP catalyzes the exchange of cholesteryl ester and triglyceride between lipoproteins and modulates HDL cholesterol levels in plasma. CETP inhibitors are potential compounds for treating coronary artery disease.

Definition

ChEBI: Evacetrapib is a benzazepine.

Biological Activity

evacetrapib is a potent and selective inhibitor of cholesteryl ester transfer protein (cetp) with ic50 value of 5.5nm [1].as a benzazepine-based inhibitor of cetp, evacetrapib is developed to increase hdl cholesterol for the treatment of coronary artery disease. evacetrapib is efficacious both in vitro and in vivo. the ic50 values of evacetrapib against cetp are 5.5nm and 26nm, respectively in the buffer assay using human recombinant cetp and in the plasma assay using human plasma cetp. in the animal model of human cetp/apoai double transgenic mouse line, oral administration of evacetrapib at 30mg/kg significantly inhibits the cetp activity as well as increases the level of hdl. besides that, the ed50 value of evacetrapib is less than 5mg/kg. compared to the previous inhibitors of cetp, evacetrapib has less side effects. it is found no to increase blood pressure zucker diabetic fatty rats and not to induce aldosterone or cortisol synthesis in h295r cells [1].

References

[1] cao g, beyer tp, zhang y, schmidt rj, chen yq, cockerham sl, zimmerman km, karathanasis sk, cannady ea, fields t, mantlo nb. evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates hdl cholesterol without inducing aldosterone or increasing blood pressure. j lipid res. 2011 dec;52(12):2169-76.