Abstract
The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.
MeSH terms
-
Angiotensin II / metabolism*
-
Angiotensin Receptor Antagonists*
-
Animals
-
Antihypertensive Agents / chemical synthesis
-
Antihypertensive Agents / chemistry
-
Antihypertensive Agents / pharmacology
-
Blood Pressure / drug effects
-
CHO Cells
-
Cricetinae
-
Crystallography, X-Ray
-
Endothelin Receptor Antagonists*
-
Isoxazoles / chemical synthesis*
-
Isoxazoles / chemistry
-
Isoxazoles / pharmacology
-
Molecular Structure
-
Radioligand Assay
-
Rats
-
Receptor, Angiotensin, Type 1
-
Receptor, Endothelin A
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis*
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology
Substances
-
Angiotensin Receptor Antagonists
-
Antihypertensive Agents
-
BMS 248360
-
Endothelin Receptor Antagonists
-
Isoxazoles
-
Receptor, Angiotensin, Type 1
-
Receptor, Endothelin A
-
Sulfonamides
-
Angiotensin II