Synthesis of LAVR-289, a new [(Z)-3-(acetoxymethyl)-4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug with pronounced antiviral activity against DNA viruses

Abstract

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC₅₀ 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC₅₀ 0.018 μM, SI 145), with a low morphological toxicity in cell culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC₅₀ 0.021 μM) and VV (EC₅₀ 0.050 μM), as well as against HSV-1 (TK-) (EC₅₀ 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.

Keywords: Acyclic nucleoside phosphonate; Broad spectrum antiviral; DNA viruses; O-(2,4-diaminopyrimidin-6-yl); Olefin cross-metathesis; Varicella-zoster virus.