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The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1990 May; Vol. 33 (5), pp. 1312-29. - Publication Year :
- 1990
-
Abstract
- A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists. Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency. The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4. The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study. Thus the AII receptor binding affinity [IC50 (microM)] of 15 microM for literature lead 1, for example, was increased to 0.018 and 0.012 microM for compounds 33 and 53. A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding. The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.
- Subjects :
- Angiotensin Receptor Antagonists
Animals
Binding Sites
Blood Pressure drug effects
Chemical Phenomena
Chemistry
Crystallography
Imidazoles metabolism
Imidazoles pharmacology
Male
Models, Molecular
Rats
Rats, Inbred Strains
Receptors, Angiotensin metabolism
Structure-Activity Relationship
Angiotensin II antagonists & inhibitors
Antihypertensive Agents chemical synthesis
Imidazoles chemical synthesis
Receptors, Angiotensin drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 33
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 2329553
- Full Text :
- https://doi.org/10.1021/jm00167a007