5′Prime;-Ester Prodrugs of the Varicella-Zoster Antiviral Agent, 6-Methoxypurine Arabinoside

Abstract

SummaryThe potent and selective activity of 6-methoxypurine arabinoside (9B[I3-D-arabinofuranosyl]-6-methoxy-9H-purine; 1) and its pharmacokinetic limitations have been described previously. In an attempt to circumvent first-pass catabolism following oral administration, a series of 5 ' -esters (2a-t) was prepared by dicyclohexyl-carbodiimide-promoted condensation with formic acid in the case of 2a, or by direct acylation of the parent nucleoside with the corresponding acyl chloride. These compounds were evaluated in rats for efficacy as oral prodrugs of 1 by measuring the amount of 1 excreted in the urine. Both aliphatic and aromatic esters exhibited a range of systemic availabilities. The substituted benzoate esters showed a correlation between the amount of 1 excreted and the electron-donating properties of the substituent. A similar relationship was observed for the relative stabilities of this series of esters to non-enzymatic hydrolysis at neutral pH. No clear relationship between systemic availability and solubility, partition coefficient, or stability was observed for the remaining esters of 1. Although significant enhancements in systemic availability were observed with some of the 5 ' -esters of this series, their limited water solubility precluded their use in intravenous formulations.

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 That Exhibits Antiviral Efficacy in SARS-CoV-2-Infected African Green Monkeys

“…A potential route of nonproductive metabolism during absorption is metabolism of the adenosine-like C -nucleobase by the action of adenosine deaminase that is highly expressed in intestinal mucosa. Indeed, ester prodrugs of adenosine analogs have been previously designed to potentially alleviate adenosine deaminase metabolism during absorption. , The metabolism of 2 and 3 by adenosine deaminase was therefore investigated in vitro, and both compounds were found to be weak substrates or inhibitors of adenosine deaminase (see Supporting Information). The in vitro data suggests that the oral bioavailability of 2 may not be significantly impacted by undesired intestinal metabolism.…”

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys

“…Indeed, ester prodrugs of adenosine analogs have been previously designed to potentially alleviate adenosine deaminase metabolism during absorption. [36][37] The metabolism of 2 and 3 by adenosine deaminase was therefore investigated in vitro and both compounds were found to be weak substrates or inhibitors of adenosine deaminase (see supporting information). The in-vitro data suggests that the oral bioavailability of 2 may not be significantly impacted by undesired intestinal metabolism.…”

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

“…In turn, derivatization of antipsychotic haloperidol by means of fatty acids of different aliphatic chain lengths (up to decanoate ester) furnished excellent prodrugs with sustained release and significantly prolonged duration of action [42]. Finally, anti-cancer drug gemcitabine esterified with various aliphatic amino acids yielded prodrugs with high affinity for the PEPT1 transporter [43], whereas a powerful anti-leukemic agent, namely 9-β-D-arabinofuranosyl guanine (ara-G), acetylated regioselectively at 5 -position rendered derivative of significantly improved solubility and bioavailability [44,45]. Other examples of prodrug strategies for cancer cell-specific targeting, extensively utilized in oncotherapies, can be found in recent review articles [46,47].…”