Design and Synthesis of Bicyclic Pyrimidinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

• DOI: 10.1021/jm701164t
• Publication Date: 2008-01-25T06:00:32Z
• Authors: Ester Muraglia; Olaf Kinzel; Cristina Gardelli; Benedetta Crescenzi; Monica Donghi; Marco Ferrara; Emanuela Nizi; Federica Orvieto; Giovanna Pescatore; Ralph Laufer; Odalys Gonzalez-Paz; Annalise Di Marco; Fabrizio Fiore; Edith Monteagudo; Massimiliano Fonsi; Peter J. Felock; Michael Rowley; Vincenzo Summa
• Keywords: Administration, Oral; Aminopyridines; Biological Availability; Stereoisomerism; Azepines; HIV Integrase; Pyrimidinones; Bridged Bicyclo Compounds, Heterocyclic; Macaca mulatta; 01 natural sciences; Cell Line; Rats; 0104 chemical sciences; 3. Good health; Structure-Activity Relationship; Dogs; HIV-1; Microsomes, Liver; Animals; Humans; HIV Integrase Inhibitors

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.