Patent Watch

March 17, 2014

HIV integrase inhibitors may be potent AIDS drugs. T. Reger and co-inventors report macrocyclic compounds, represented generally by formula 1, that are HIV integrase inhibitors. These compounds may be useful for treating HIV infections and AIDS.

An essential step in the replication process of HIV is the integration of the proviral DNA into the host DNA in human T-lymphoid and monocytoid cells. It is believed that integration is mediated by the retroviral integrase, an enzyme produced by the retrovirus that allows its genetic material to be integrated into the DNA of the infected host cell. 

General formula and representative examples of HIV integrase inhibitors

Evidence obtained from nucleotide sequencing and the amino acid sequence homology of HIV shows that three enzymes (reverse transcriptase, integrase, and an HIV protease) are essential for HIV replication. Thus, inhibiting any of these enzymes is a pharmaceutical target for treating HIV infections.

Known HIV replication inhibitors are also effective for treating AIDS. For example, azidothymidine (AZT) and efavirenz are reverse transcriptase inhibitors, and indinavir and nelfinavir are protease inhibitors. The compounds disclosed by the inventors show activity as HIV replication inhibitors by inhibiting HIV integrase. They may also be effective for treating AIDS.

The inventors describe the synthesis and structures of 28 examples of formula 1, including examples 2, 3, and 4. They used the in vitro inhibition of HIV replication assay in the presence of 10% normal human serum to evaluate these compounds. The IC95 values of the 28 examples ranged from 6 to 2262 nM. The data for three representative examples are listed in the table.

Example IC95 (nM)
2 2262
3 9
4 6

(Merck Sharp & Dohme [Rahway, NJ]. WIPO Publication 2014008636, Jan. 16, 2014; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.