Discovery of viral primases as drug targets: Compound based target elucidation, validation, and advancement to the clinic

MEDI 273

Jay P. Powers, jppowers@amgen.com1, J. Adrian2, X. Chen2, T. D. Cushing2, H. Dimaio2, J. C. Jaen2, L. Liang2, V. Mayorga2, S. Miao2, M. G. Peterson2, F. Spector2, C. Stein2, M. Wright2, and Q. Ye2. (1) Department of Chemistry Research & Discovery, Amgen, Inc, 1120 Veterans Blvd., South San Francisco, CA 94080, (2) Amgen Inc
The existing treatments for human cytomegalovirus (HCMV) suffer from a lack of oral bioavailability, as well as dose-limiting toxicity. We have identified a series of novel non-nucleoside inhibitors of HCMV replication, which are more potent than either ganciclovir (GCV) or cidofovir (CDV). High-throughput cell based screening with a recombinant HCMV assay resulted in the discovery of a novel series of non-nucleoside inhibitors, which were found to be selective for inhibiting HCMV replication relative to other viruses. Genetic and biochemical studies demonstrated the viral UL70 primase to be the biochemical target of these compounds. Structure-activity relationship studies around this series suggests that compounds in this class are specific, covalent modifiers of HCMV primase. SAR studies resulted in potent (IC50: 0.02-0.10 uM) inhibitors of HCMV replication. Furthermore, optimization of antiviral activity, pharmacokinetic and physicochemical properties resulted in a potent (IC50: 0.070 uM, viral replication), orally bioavailable antiviral agent which was advanced to clinical trials for the treatment of HCMV-related disease.
 

Reverse Pharmacology: The Role of Medicinal Chemistry in Novel Target Identification
1:30 PM-4:50 PM, Monday, 11 September 2006 Moscone Center -- Room 102, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006