Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ET(B) antagonists containing a diphenylmethylamine acetamide side chain.
The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ET(A)-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ET(B) receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ET(B) affinity and also boost the ET(A)/ET(B) activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group (10h). Combining these features with modification of the 2-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ET(B) receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.
Liu
G
G
Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. gang.liu@abbott.com
Kozmina
N S
NS
Winn
M
M
von Geldern
T W
TW
Chiou
W J
WJ
Dixon
D B
DB
Nguyen
B
B
Marsh
K C
KC
Opgenorth
T J
TJ
D000081:Acetamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000284:Administration, Oral; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D006801:Humans; D008744:Methylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
C121696:A 308165; D000081:Acetamides; D065128:Endothelin Receptor Antagonists; D008744:Methylamines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011392:Proline; D000077868:Atrasentan