Selection of a Derivative of the Antiviral Agent 9-[(1,3-Dihydroxy-2-propoxy)-methyl]Guanine (DHPG) with Improved Oral Absorption
- 1 January 1987
- journal article
- Published by Springer Science and Business Media LLC in Pharmaceutical Research
- Vol. 4 (2), 120-125
- https://doi.org/10.1023/a:1016462801968
Abstract
Various diesters of 9-[(l,3-dihydroxy-2-propoxy)-methyl]guanine (DHPG) were screened in order to identify a derivative with improved oral absorption. The solubilities and dissolution rates decreased with increasing chain length and branching of the ester group. However, the dipropionate ester showed an anomalously faster dissolution rate. The rates of hydrolysis to DHPG in the presence of intestinal homogenates were found to increase with increasing carbon number for the straight-chain alkyl esters and decreased with branching. The shorter-chain alkyl esters were relatively more stable in intestinal homogenates than in liver homogenates. Therefore they may have a better membrane permeability than DHPG due to their intact ester group. The hydrolysis rates in human blood increased with increasing carbon number for the straight-chain alkyl esters. The dipropionate ester appeared to be the most promising derivative because of its rapid dissolution rate, slower hydrolysis in the intestine, and rapid conversion to DHPG in liver and blood.Keywords
This publication has 15 references indexed in Scilit:
- A Dual-Column HPLC Method for the Simultaneous Determination of DHPG (9-[(1,3-Dihydroxy-2-Propoxy)Methyl]Guanine) and Its Mono and Diesters in Biological SamplesJournal of Chromatographic Science, 1985
- Activity of esterase in the hydrolysis of 3',5'-diesters of 5-fluoro-2'-deoxyuridine in relation to the structure of the diester prodrugs.CHEMICAL & PHARMACEUTICAL BULLETIN, 1985
- Anti-herpesvirus activity of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanineAntimicrobial Agents and Chemotherapy, 1983
- 9-(1,3-Dihydroxy-2-propoxymethyl)guanine: a new potent and selective antiherpes agentJournal of Medicinal Chemistry, 1983
- Low-Melting Phenytoin Prodrugs as Alternative Oral Delivery Modes for Phenytoin: A Model for Other High-Melting Sparingly Water-Soluble DrugsJournal of Pharmaceutical Sciences, 1983
- Development of lipophilic prodrugs of mitomycin C. III. Physicochemical and biological properties of newly synthesized alkoxycarbonyl derivatives.CHEMICAL & PHARMACEUTICAL BULLETIN, 1983
- Prodrugs of 9-(.beta.-D-arabinofuranosyl)adenine. 2. Synthesis and evaluation of a number of 2',3'- and 3',5'-di-O-acyl derivativesJournal of Medicinal Chemistry, 1979
- Prodrugs of 9-.beta.-D-arabinofuranosyladenine. 1. Synthesis and evaluation of some 5'-(O-acyl) derivativesJournal of Medicinal Chemistry, 1978
- Rationale for Design of Biologically Reversible Drug Derivatives: ProdrugsJournal of Pharmaceutical Sciences, 1975
- Improved Holder for Intrinsic Dissolution Rate StudiesJournal of Pharmaceutical Sciences, 1965