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 <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.
Guillon
Christophe D
CD
Department of Chemistry, 6 East Packer Avenue, Lehigh University, Bethlehem, PA 18015, USA. chg3@lehigh.edu
Koppel
Gary A
GA
Brownstein
Michael J
MJ
Chaney
Michael O
MO
Ferris
Craig F
CF
Lu
Shi-Fang
SF
Fabio
Karine M
KM
Miller
Marvin J
MJ
Heindel
Ned D
ND
Hunden
David C
DC
Cooper
Robin D G
RD
Kaldor
Stephen W
SW
Skelton
Jeffrey J
JJ
Dressman
Bruce A
BA
Clay
Michael P
MP
Steinberg
Mitchell I
MI
Bruns
Robert F
RF
Simon
Neal G
NG
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
C116379:2-azetidinone; D065092:Antidiuretic Hormone Receptor Antagonists; D001384:Azetidines