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Azetidinones as vasopressin V1a antagonists |
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| Authors: | Guillon Christophe D Koppel Gary A Brownstein Michael J Chaney Michael O Ferris Craig F Lu Shi-Fang Fabio Karine M Miller Marvin J Heindel Ned D Hunden David C Cooper Robin D G Kaldor Stephen W Skelton Jeffrey J Dressman Bruce A Clay Michael P Steinberg Mitchell I Bruns Robert F Simon Neal G |
| Institution: | Department of Chemistry, 6 East Packer Avenue, Lehigh University, Bethlehem, PA 18015, USA. chg3@lehigh.edu |
| 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. |
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