Abstract
A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. Early compounds in this series were found to show poor gastrointestinal absorption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding potential, through a reduction in the number of H-bond donors and acceptors, could increase absorption of the molecules. There was a correlation between calculated H-bonding capacity and rate of permeability across Caco-2 monolayers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the requirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Species differences were observed between the absorption of compound 7a in rat and dog and also in the extent of conversion to the acid metabolite. Absorption was estimated at 30% in rat and 100% in dog. Approximately 30% of the absorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog.
Footnotes
- Abbreviations used are::
- ETA
- endothelin A
- ETB
- endothelin B
- DMSO
- dimethyl sulfoxide
- HPLC
- high-performance liquid chromatography
- Kel
- terminal elimination rate constant
- AUC
- area under the curve
- CL
- clearance
- C log P
- calculated log P
- Cad
- hydrogen bond free energy
- HBA
- hydrogen-bond acceptor
- HBD
- hydrogen-bond donor
- Received May 8, 2001.
- Accepted July 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|