Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids.
The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J. Med. Chem. 1992, 35, 3858). Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II. Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity. SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency. Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented. The parent diacid analog, SK&F 108566 or (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazole-5-yl]-2-[(2- thienyl)methyl]propenoic acid, is currently in clinical development for the treatment of hypertension.
Keenan
R M
RM
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Weinstock
J
J
Finkelstein
J A
JA
Franz
R G
RG
Gaitanopoulos
D E
DE
Girard
G R
GR
Hill
D T
DT
Morgan
T M
TM
Samanen
J M
JM
Peishoff
C E
CE
D000179:Acrylates / Q000138:chemical synthesis* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan