Selective endothelin A receptor antagonists. 3. Discovery and structure-activity relationships of a series of 4-phenoxybutanoic acid derivatives.
The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)b utanoi c acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.
Astles
P C
PC
Rhône-Poulenc Rorer, Dagenham Research Centre, Rainham Road South, Dagenham, Essex RM10 7XS, UK.
Brealey
C
C
Brown
T J
TJ
Facchini
V
V
Handscombe
C
C
Harris
N V
NV
McCarthy
C
C
McLay
I M
IM
Porter
B
B
Roach
A G
AG
Sargent
C
C
Smith
C
C
Walsh
R J
RJ
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003655:Decerebrate State; D065128:Endothelin Receptor Antagonists; D007275:Injections, Intravenous; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
C113343:4-(2-cyano-5-(3-pyridylmethoxy)phenoxy)-4-(2-methylphenyl)butanoic acid; D065128:Endothelin Receptor Antagonists; D010654:Phenylbutyrates; D011725:Pyridines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B