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

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.

Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

“…With unsubstituted benzylmethylamine derivatives showing nanomolar enzymatic inhibition profiles similar to those of derivatives with saturated ring side chains (though little inhibition of viral replication in cell culture), it was decided that the 2- β -nitrogen would be modified to optimize physiochemical properties of pyrimidone compounds [61]. For example, introduction of a sulfonamide (compound 17) resulted in a low shift in activity in serum conditions, suggesting an increased level of cell permeability.…”

Diketoacid Inhibitors of HIV-1 Integrase: From L-708,906 to Raltegravir and Beyond

“…Later studies at Merck have looked at the effect of further rigidification of this skeleton [70,80] and at substitution of the pendent benzylamine group [81]. The most potent inhibitors in each of these series are 46 and 47, respectively (Fig.…”

Targeting Integration beyond Strand Transfer: Development of Second‐Generation HIV Integrase Inhibitors

“…Only after binding and processing viral DNA, INSTIs bind to integrase and specifically block strand transfer. Since the publication of the first diketo acid [33], many other INSTIs from different chemical classes have been developed: naphthyridines, pyrimidinone carboxamides, bicyclic pyrimidones, and pyrrolloquinolones [34][35][36][37][38]. These molecules share a dimetal chelating entity in their pharmacophore (Figure 3.3).…”