Back to Search
Start Over
Design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2008 Feb 28; Vol. 51 (4), pp. 861-74. Date of Electronic Publication: 2008 Jan 25. - Publication Year :
- 2008
-
Abstract
- HIV integrase is one of the three enzymes encoded by HIV genome and is essential for viral replication, but integrase inhibitors as marketed drugs have just very recently started to emerge. In this study, we show the evolution from the N-methylpyrimidinone structure to bicyclic pyrimidinones. Introduction of a suitably substituted amino moiety modulated the physical-chemical properties of the molecules and conferred nanomolar activity in the inhibition of spread of HIV-1 infection in cell culture. An extensive SAR study led to sulfamide (R)- 22b, which inhibited the strand transfer with an IC50 of 7 nM and HIV infection in MT4 cells with a CIC95 of 44 nM, and ketoamide (S)- 28c that inhibited strand transfer with an IC50 of 12 nM and the HIV infection in MT4 cells with a CIC95 of 13 nM and exhibited a good pharmacokinetic profile when dosed orally to preclinical species.
- Subjects :
- Administration, Oral
Aminopyridines pharmacokinetics
Aminopyridines pharmacology
Animals
Azepines pharmacokinetics
Azepines pharmacology
Biological Availability
Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Cell Line
Dogs
HIV Integrase genetics
HIV Integrase Inhibitors pharmacokinetics
HIV Integrase Inhibitors pharmacology
HIV-1 drug effects
Humans
Macaca mulatta
Microsomes, Liver metabolism
Pyrimidinones pharmacokinetics
Pyrimidinones pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
Aminopyridines chemical synthesis
Azepines chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic chemical synthesis
HIV Integrase metabolism
HIV Integrase Inhibitors chemical synthesis
Pyrimidinones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 51
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18217703
- Full Text :
- https://doi.org/10.1021/jm701164t