Imidazole-5-acrylic acids: potent nonpeptide angiotensin II receptor antagonists designed using a novel peptide pharmacophore model.
A series of novel nonpeptide angiotensin II receptor antagonists containing a substituted (E)-acrylic acid has been developed. The overlay of 1, an imidazole-5-acetic acid found in the patent literature, on a novel pharmacophore model of AII suggested that extension of the acid side chain and attachment of a second aryl residue to mimic the C-terminal phenylalanine region of AII would lead to increased activity. A study of extended acid side chains at C-5 of the imidazole nucleus led to the discovery of the (E)-acrylic acid 5 as a promising starting point for further exploration. As predicted by the modeling, substitution of a benzyl group on the acrylic acid side chain to mimic the phenylalanine gave increased potency. An extensive study of the SAR of the newly introduced aromatic ring revealed that electron-rich heteroaryl rings provided improved activity, most notably in the in vivo rat models. Compound 40, (E)-3-[2-butyl-1- [(2-chlorophenyl)methyl]imidazol-5-yl]-2-[(2-thienyl)methyl]-2- propenoic acid, has been shown to be a potent, competitive, and orally active small molecule AT-1 receptor antagonist. It exhibits a 2 orders of magnitude increase in binding affinity and a 10-fold improvement in in vivo potency as compared to compound 1 and represents an important milestone in the development of even more potent nonpeptide angiotensin II receptor antagonists.
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
Hempel
J
J
D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D015195:Drug Design; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles