1. Azetidinones as vasopressin V1a antagonists.
- Author
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Guillon CD, Koppel GA, Brownstein MJ, Chaney MO, Ferris CF, Lu SF, Fabio KM, Miller MJ, Heindel ND, Hunden DC, Cooper RD, Kaldor SW, Skelton JJ, Dressman BA, Clay MP, Steinberg MI, Bruns RF, and Simon NG
- Subjects
- Animals, Azetidines blood, Azetidines pharmacokinetics, Brain metabolism, CHO Cells, Cricetinae, Cricetulus, Dogs, Humans, Magnetic Resonance Spectroscopy, Models, Molecular, Rats, Spectrometry, Mass, Fast Atom Bombardment, Antidiuretic Hormone Receptor Antagonists, Azetidines pharmacology
- Abstract
The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.
- Published
- 2007
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