Wild CT, Kilgore NR, Reddick MS, Asfaw YD, Salzwedel KD, Turpin JA, Xie L, Lee KH, Smith PC, Allaway GP, Martin DE; International Conference on AIDS.
Int Conf AIDS. 2002 Jul 7-12; 14: abstract no. TuPeB4435.
Panacos Pharmaceuticals Inc., Gaithersburg, MD, United States
BACKGROUND: The dicamphanoyl khellactone (DCK) compounds potently inhibit replication of HIV-1 by a novel mechanism of action compared to approved drugs. They do not inhibit RNA-dependent DNA polymerase activity of HIV-1 RT, but block the production of double-stranded DNA. Their precise molecular target is the subject of ongoing studies. PA-344B is a new analog in this family with improved solubility and in vivo disposition. Its in vitro and in vivo properties are described in this report. METHODS: PA-344B was analyzed for potency against a panel of primary HIV-1 isolates, including drug resistant strains, propagated in PBMCs. Binding to human plasma proteins was analyzed by a standard filtration method. In vivo disposition was examined in rats and dogs following IV or PO administration at 10-25 mg/kg. In vitro metabolism of the compound was analyzed following incubation with liver microsomes from several species. RESULTS: PA-344B inhibited replication of all primary HIV-1 isolates tested, including AZT-resistant strains, with a mean IC50 of 40nM. Comparison with the mean in vitro cytotoxicity concentration of 50microM gave a selectivity index of >1,000. Binding to human plasma proteins was moderate (80-85% bound). Following IV administration to rats PA-344B had a half-life of approximately 3 hours. Oral bioavailability was around 15% in rats but lower in dogs. This may be explained by a higher rate of first pass metabolism in dogs compared to rats. In vitro metabolism studies using liver microsomes indicated that dogs have a faster rate of metabolism than rats while metabolism by human liver microsomes was the slowest. CONCLUSIONS: PA-344B exhibits in vitro and in vivo properties that support its further development as an HIV drug candidate. Pre-clinical toxicology studies are in progress with the goal of filing an IND and initiating clinical testing during 2002.
Publication Types:
Keywords:
- Administration, Oral
- Animals
- Biological Availability
- Dogs
- HIV-1
- Human Development
- Humans
- In Vitro
- Microsomes, Liver
- Pharmaceutical Preparations
- RNA-Directed DNA Polymerase
- Rats
- Rats, Sprague-Dawley
- Solubility
- Zidovudine
- growth & development
- metabolism
- p-Aminosalicylic Acid
Other ID:
UI: 102253509
From Meeting Abstracts