ABSTRACT
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/pharmacology , Endothelin A Receptor Antagonists , Isoxazoles/chemistry , Isoxazoles/pharmacology , Receptor, Angiotensin, Type 1/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Biological Availability , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Dogs , Humans , Hypertension/drug therapy , Irbesartan , Isoxazoles/pharmacokinetics , Macaca fascicularis , Male , Rats , Rats, Inbred SHR , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Tetrazoles/chemistry , Tetrazoles/pharmacologyABSTRACT
A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ET(A) receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension.
Subject(s)
Angiotensin Receptor Antagonists , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Endothelin Receptor Antagonists , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Binding Sites/drug effects , Blood Pressure/drug effects , Caco-2 Cells , Drug Design , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Indicators and Reagents , Male , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1 , Receptor, Endothelin A , Structure-Activity RelationshipABSTRACT
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.
