Azetidinones as vasopressin V1a antagonists

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 <1 nM and brain levels after oral dosing ∼100-fold higher than receptor affinities.Figure optionsDownload as PowerPoint slide

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