Discovery of 1,6-Naphthyridines as a Novel Class of Potent and Selective Human Cytomegalovirus Inhibitors

• Published in: Journal of medicinal chemistry 1999-08, Vol.42 (16), p.3023-3025
• Main Authors: Chan, Laval, Jin, Haolun, Stefanac, Tomislav, Lavallée, Jean-François, Falardeau, Guy, Wang, Wei, Bédard, Jean, May, Suzanne, Yuen, Leonard
• Format: Article
• Language: English
• Subjects: 1,6-Naphthyridines; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - toxicity; Biological and medical sciences; Cell Line; Cytomegalovirus - drug effects; Human cytomegalovirus; Humans; Inhibitory Concentration 50; Medical sciences; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Naphthyridines - toxicity; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9902483

Human cytomegalovirus (HCMV) is a species-specific DNA virus belonging to the herpesviridae family. Although HCMV infection is prevalent in the majority of the adult population, manifestation of disease is rare in immunocompetent individuals. However, in immunocompromised persons such as AIDS patients and organ transplant recipients, infection can result in retinitis, pneumonitis, or other afflictions. The current anti-HCMV agents on the market (foscarnet, ganciclovir (GCV), cidofovir (CDV), and formivirsen) suffer from various toxicities and poor oral bioavailability. Since management of HCMV disease often requires prophylactic treatment or maintenance therapy, adverse effects due to drug are a concern in these cases. Furthermore, the emergence of strains resistant to the currently used therapies has been observed. There is therefore a need for novel antiviral agents with a more favorable safety profile. As part of our ongoing interest in the area of antiviral research, we have screened numerous compounds, both from in-house collections and from external sources, against a variety of viruses. This led to the identification of 1,6-naphthyridine 1 as an inhibitor of HCMV with a potency and selectivity similar to that of GCV. In this Communication, the design and synthesis of analogues of 1, as well as the results of preliminary structure-activity relationship (SAR) studies, will be described.