Enhancing the aqueous solubility of d4T-based phosphoramidate prodrugs

  • Bioorg Med Chem Lett. 2000 Feb 21;10(4):381-4. doi: 10.1016/s0960-894x(99)00701-5.
A Siddiqui  1 ,  C McGuigan ,  C Ballatore ,  S Srinivasan ,  E De Clercq ,  J Balzarini
Affiliations
  • 1. Welsh School of Pharmacy, Cardiff University, UK.
PMID: 10714505 DOI: 10.1016/s0960-894x(99)00701-5
Abstract

A range of polyether para-substituted phosphoramidates were synthesised and found to have substantially elevated aqueous solubilities compared to the underivatised parent prodrug. A 30-fold increase in aqueous solubility could be achieved without a substantial decrease of in vitro activity against HIV-1. Replacement of the aryl (i.e. phenolic) moiety by tyrosine led to a substantial enhancement in aqueous solubility but also to a decrease in Antiviral potency. A previously unobserved trend was identified, relating increased aryl substituent steric bulk to decreased Antiviral activity.