Selective endothelin A receptor antagonists. 4. Discovery and structure-activity relationships of stilbene acid and alcohol derivatives.
This publication describes the synthesis and optimization of a novel series of stilbene endothelin antagonists. Analysis of the SAR established for previous papers in this series prompted the design and synthesis of (Z)-4-phenyl-5-(3-benzyloxyphenyl)pent-4-enoic acid 3 which was found to be a moderately active inhibitor of the binding of [125I]ET-1 to ETA receptors with an IC50 of 6 microM. More interestingly, the intermediate compound (E)-2-phenyl-3-(3-benzyloxyphenyl)propenoic acid 5 was equiactive with 3. Optimization of 5 resulted in the preparation of (E)-2-phenyl-3-(2-cyano-5-(thien-3-ylmethoxy))phenylprope noic acid 18 (RPR111723) which had an IC50 in the binding assay of 80 nM on the ETA receptor and a pKB of 6.5 in the functional assay, measured on rat aortic strips. Reduction of the acid group of 5 gave the first nonacidic ETA antagonist in our series, (E)-2-phenyl-3-(3-benzyloxyphenoxy)prop2-enol 6 with an IC50 of 20 microM. Optimization of 6 resulted in the preparation of 2-(2-methylphenyl)-3-(2-cyano-5-(thien-3-ylmethyl)phenyl)pro p-2-enol 33 with an IC50 of 300 nM on the ETA receptor.
Rhône-Poulenc Rorer, Dagenham Research Centre, Rainham Road South, Dagenham, Essex, RM10 7XS U.K.
P C
PC
Astles
T J
TJ
Brown
F
F
Halley
C M
CM
Handscombe
N V
NV
Harris
C
C
McCarthy
I M
IM
McLay
P
P
Lockey
T
T
Majid
B
B
Porter
A G
AG
Roach
C
C
Smith
R
R
Walsh
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship
D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; C113344:RPR 111723; D044022:Receptor, Endothelin A