Nucleosides represent a well-established and extremely important class of drugs in the treatment of infectious diseases, including HIV and HCV. All of these nucleosides require kinase-mediated phosphorylation in target cells to form their active triphosphate (or phosphonate diphosphate) anabolites to inhibit viral replication. The initial phosphorylation step is often rate limiting, therefore one effective method commonly employed to bypass this step is to prepare the monophosphate or phosphonate forms of the nucleoside. However, monophosphates and phosphonates are highly polar anionic functional groups that do not readily cross biological membranes. Prodrug approaches that mask the charge overcome this limitation and have proven to improve the permeability of these molecules and subsequently their intracellular delivery. While early interest in prodrugs was focused on developing molecules with improved oral bioavailability, attention has shifted in recent years to the design of prodrugs that target intracellular enzymes to liberate the parent molecule inside target cells. Herein we describe the de novo rational design and discovery of two structurally novel phosphonate prodrug classes using tenofovir as a prototype parent molecule. A thiolactone/lactone phosphonamide series was identified in which a carboxylate group derived from the intracellular hydrolysis of the thiolactone or lactone moiety potentially triggers the conversion to the parent drug. This series exhibits double-digit nanomolar potency in a viral replication inhibition cell-based assay. A novel phosphinic amide prodrug class displaying single-digit nanomolar potency in vitro was also discovered. This class was found to be very stable in relevant biological and simulated media, likely as a result of the unique P-C bond in the promoiety. In addition to these two classes, other structurally novel phosphonate prodrugs were also identified. Prodrug SAR, synthesis, and in vitro and in vivo data will be presented.

Discovery of novel phosphonate prodrugs by de novo rational design

256th National Meeting (2018)

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