Discovery and Synthesis of HIV Integrase Inhibitors: Development of Potent and Orally Bioavailable N-Methyl Pyrimidones
Citations Over TimeTop 10% of 2007 papers
Abstract
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Related Papers
- Characterization and structural analysis of HIV-1 integrase conservation.(2009)
- → Evolution of Integrase Resistance During Failure of Integrase Inhibitor-Based Antiretroviral Therapy(2010)73 cited
- → Integrase inhibitors in the treatment of HIV-1 infection(2010)56 cited
- → Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors(2013)22 cited
- → Synthesis and HIV-1 Integrase Inhibition Activity of some N-Arylindoles(2008)46 cited