Patent Watch

October 21, 2013

Endothelial lipase inhibitors are potential cardiovascular disease drugs. Inventors M. Greco and H. Ye disclose tricyclic indole derivatives, represented generally by formula 1 (Figure 1), that are endothelial lipase (EL) inhibitors and may be useful for the treating cardiovascular disorders. In the formula, structure A represents a five- to seven-membered saturated ring.

Studies have shown an inverse relationship between plasma levels of high-density lipoprotein cholesterol (HDL-C) and the risk of atherosclerosis and coronary heart disease. Atherosclerosis is a condition in which an artery wall thickens because of the accumulation of fatty materials such as cholesterol and triglycerides.

EL is a serine-phospholipase that is synthesized in endothelial cells. It is a recently discovered member of the triglyceride lipase family that was first characterized and cloned in 1999. Earlier studies indicated that EL catalyzes the hydrolysis of HDL phospholipids, which lower HDL levels. 

General formula and four examples of potential endothelial lipase inhibitors

Mouse studies have established the role of EL in regulating HDL cholesterol. EL knockout mice show elevated HDL cholesterol levels relative to wild-type mice. Overexpression of the human EL gene in mice livers markedly reduces plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-1. Other recent studies suggest that EL may cause inflammation and be involved in atherogenesis.

These findings suggest that EL inhibition is an attractive clinical target for treating cardiovascular disorders. The EL inhibitors described in the patent application may elevate HDL-C plasma levels and consequently reduce atherosclerosis and cardiovascular disease. The inventors prepared 28 compounds with formula 1; structures 25 shown in Figure 1 are representative examples.

The inventors evaluated the 28 compounds by using human and mouse EL assays. The IC50 results for examples 25 are shown in the table. The lowest values were obtained from compounds 2, 3, and 4 and the highest from compound 5.

Example Human EL assay,
IC50 (μM)
Mouse EL assay,
IC50 (μM)
2 0.014 0.017
3 0.004 0.004
4 0.039 0.031
5 33.335 33.335

The compounds of formula 1 were prepared by the reaction of intermediates with general structure 6 with oxiranes 7 in hexafluoro-2-propanol (Figure 2). Intermediate 8 was then dehydrated with SO2Cl or POCl3.

Synthesis of compounds of formula 1

(Janssen Pharmaceutica [Beerse, Belgium]. WIPO Publication 2013123277, Aug 22, 2013; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.