Highly active anti-retroviral therapy (HAART) significantly reduces human immunodificiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodificiency syndome (AIDS) related mortality.  Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistent viral strains.  Next generation NNRTIs are sought which are effective against these mutant forms of the HIV virus.  Pyridones were evaluated as an acyclic conformational constraint to replace the aryl ether core of MK-4965 and the more rigid constraint of MK-6186.  The resulting pyridone compounds are potent inhibitors of HIV RT and have antiviral activity in cell culture that is superior to other next generation NNRTIs.  The 4-trifluoromethyl pyridone analog displays adequate pharmacokinetic properties at lower doses but was unable to achieve exposure goals at higher doses.  The preparation of prodrugs that were designed to enhance solubility resulted in increased exposures following oral administration to preclinical species.

Design and synthesis of pyridone inhibitors of non-nucleoside reverse transciptase

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.