title: Azetidinones as vasopressin V1a antagonists.
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.
authors.affiliation: Department of Chemistry, 6 East Packer Avenue, Lehigh University, Bethlehem, PA 18015, USA. chg3@lehigh.edu
authors.forename: Christophe D
authors.initials: CD
authors.lastname: Guillon
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koppel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brownstein
authors.forename: Michael O
authors.initials: MO
authors.lastname: Chaney
authors.forename: Craig F
authors.initials: CF
authors.lastname: Ferris
authors.forename: Shi-Fang
authors.initials: SF
authors.lastname: Lu
authors.forename: Karine M
authors.initials: KM
authors.lastname: Fabio
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Ned D
authors.initials: ND
authors.lastname: Heindel
authors.forename: David C
authors.initials: DC
authors.lastname: Hunden
authors.forename: Robin D G
authors.initials: RD
authors.lastname: Cooper
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Kaldor
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Skelton
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Dressman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clay
authors.forename: Mitchell I
authors.initials: MI
authors.lastname: Steinberg
authors.forename: Robert F
authors.initials: RF
authors.lastname: Bruns
authors.forename: Neal G
authors.initials: NG
authors.lastname: Simon
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D051381:Rats; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: C116379:2-azetidinone; D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines