Azetidinones as vasopressin V1a antagonists

  • Bioorg Med Chem. 2007 Mar 1;15(5):2054-80. doi: 10.1016/j.bmc.2006.12.031.
Christophe D Guillon  1 ,  Gary A Koppel ,  Michael J Brownstein ,  Michael O Chaney ,  Craig F Ferris ,  Shi-Fang Lu ,  Karine M Fabio ,  Marvin J Miller ,  Ned D Heindel ,  David C Hunden ,  Robin D G Cooper ,  Stephen W Kaldor ,  Jeffrey J Skelton ,  Bruce A Dressman ,  Michael P Clay ,  Mitchell I Steinberg ,  Robert F Bruns ,  Neal G Simon
Affiliations
  • 1. Department of Chemistry, 6 East Packer Avenue, Lehigh University, Bethlehem, PA 18015, USA. [email protected]
PMID: 17234419 DOI: 10.1016/j.bmc.2006.12.031
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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