Discovery of N-Isoxazolyl Biphenylsulfonamides as Potent Dual Angiotensin II and Endothelin A Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 45; no. 18; pp. 3829 - 3835
• Main Authors: Murugesan, Natesan, Tellew, John E, Gu, Zhengxiang, Kunst, Bridgette L, Fadnis, Leena, Cornelius, Lyndon A, Baska, Rose Ann F, Yang, Yifan, Beyer, Sophie M, Monshizadegan, Hossain, Dickinson, Kenneth E, Panchal, Balkrushna, Valentine, Maria T, Chong, Saeho, Morrison, Richard A, Carlson, Kenneth E, Powell, James R, Moreland, Suzanne, Barrish, Joel C, Kowala, Mark C, Macor, John E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29-08-2002
• Subjects: Angiotensin II - metabolism; Angiotensin Receptor Antagonists; Animals; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Cardiovascular system; CHO Cells; Cricetinae; Crystallography, X-Ray; Endothelin Receptor Antagonists; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Radioligand Assay; Rats; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Isoxazole derivatives; Rat; Nitrogen heterocycle; Lactam; Selectivity; ETA endothelin receptor; Structure activity relation; Bicyclic compound; Blood pressure; Antagonist; Chemical synthesis; Oxygen nitrogen heterocycle; Human; Sulfonamide; Rodentia; Oral administration; AT1 angiotensin receptor; In vitro; Spiran; In vivo; Vertebrata; Mammalia; Biphenyl derivatives; Animal; Affinity; Antihypertensive agent; Angiotensin antagonist; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020138n

The ETA 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 AT1 receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT1 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 AT1 and ETA receptors. Compound 15 represents a new approach to treating hypertension.