Patent Watch

February 17, 2014

A selective EP4 antagonist may be useful for treating arthritis and arthritic pain. Inventors M. A. Schiffler and J. S. York describe N-phenoxyethylpiperidine derivatives that are represented generally by formula 1. These compounds are selective prostaglandin E receptor 4 (EP4) antagonists that may be useful for treating inflammatory conditions such as osteoarthritis and rheumatoid arthritis and the pain associated with these conditions.

The more than 1000 forms of the inflammatory joint disorder arthritis make it a leading cause of disability. This disorder is often treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors. These drugs, however, cause adverse cardiovascular and/or gastrointestinal effects that limit their use for patients who suffer from cardiovascular conditions such as hypertension. Alternative treatments for osteoarthritis and rheumatoid arthritis are needed that do not cause the side effects of the current drugs.

General formula and representative examples of EP4 antagonists

Prostaglandin E2 (PGE2), an inflammatory mediator, is released at the site of tissue inflammation. Its activities are mediated by four G-protein–coupled EP receptors: EP1, EP2, EP3, and EP4. Researchers have identified EP4 as the primary receptor in inflammatory joint pain in rodent models of rheumatoid arthritis and osteoarthritis. Therefore, the use of EP4 antagonists such as the inventors’ compounds is potentially useful for treating arthritis and the pain it causes. Because EP4 antagonism does not interfere with the biosynthesis of prostanoids, a selective EP4 antagonist may not cause the cardiovascular side effects of NSAIDs and COX-2 inhibitors.

The inventors report the synthesis and structures of nine examples, including compounds 24 shown in the figure. They used the following biological assays to test the compounds:

  • in vitro binding to human EP1, EP2, EP3, and EP4;
  • in vitro human EP4 functional antagonist activity;
  • in vitro rat EP4 functional antagonist activity; and
  • in vitro antagonist activity in human whole blood.

Although all nine examples were tested, the inventors report specific assay results only for example 2. The binding assay results for this example are listed in Table 1. Table 2 contains the results from the other assays.

Table 1

Test hEp1 hEp2 hEp3 hEp4
Ki (nM) >17,500 1550 ± 1860 >14,000 54 ± 27
n 1 3 1 7

Table 2

Test hEP4 Rat EP4 Human
whole blood
IC50 (nM) 6.9 ± 2.5 15 123 ± 88
n 5 1 12

(Eli Lilly [Indianapolis]. WIPO Publication 2014004229, Jan. 3, 2014; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.