Potent and selective non-benzodioxole-containing endothelin-A receptor antagonists.
The benzodioxole ((methylenedioxy)benzene) group is present in a number of endothelin (ET) receptor antagonists thus far reported. As part of our own endothelin antagonist program we have developed (2R*,3R*,4S*)-1-(N,N-dibutylacetamido)-4-(1,3-benzodioxol-5- yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (A-127722). This is a potent antagonist, binding to the ETA and ETB receptor subtypes with affinities (IC50) of 0.4 and 520 nM, respectively, and also contains the aforementioned benzodioxole. While this compound was seemingly optimized at its N-terminus, no effort had been directed toward understanding the contributions to binding affinity or receptor subtype selectivity conferred by the benzodioxole. Substitution by 1- or 2-naphthyl yielded weak antagonists. Oxygenated benzenes, such as p-anisyl, were potent compounds with IC50s in the low-nanomolar range. Simple deletion of either of the two oxygen atoms (dihydrobenzofurans) yielded extremely potent agents, possessing subnanomolar affinity for the ETA receptor. Additionally, the compounds showed enhanced selectivity, binding to the ETB receptor subtype in the micromolar range. This paper describes the development of this novel class of compounds.
Tasker
A S
AS
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Sorensen
B K
BK
Jae
H S
HS
Winn
M
M
von Geldern
T W
TW
Dixon
D B
DB
Chiou
W J
WJ
Dayton
B D
BD
Calzadila
S
S
Hernandez
L
L
Marsh
K C
KC
WuWong
J R
JR
Opgenorth
T J
TJ
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004149:Dioxoles / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008968:Molecular Conformation; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship
D000081:Acetamides; D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D011392:Proline; C040539:1,3-benzodioxole