Murugesan, Natesan; Gu, Zhengxiang; Fadnis, Leena; Tellew, John E.; Baska, Rose Ann F.; Yang, Yifan; Beyer, Sophie M.; Monshizadegan, Hossain; Dickinson, Kenneth E.; Valentine, Maria T.; Humphreys, W. Griffith; Lan, Shih-Jung; Ewing, William R.; Carlson, Kenneth E.; Kowala, Mark C.; Zahler, Robert; Macor, John E. published the artcile< Dual Angiotensin II and Endothelin A Receptor Antagonists: Synthesis of 2'-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics>, Synthetic Route of 89003-95-2, the main research area is angiotensin endothelin antagonist isoxazolyl biphenylsulfonamide preparation pharmacokinetics; antihypertensive synergism angiotensin endothelin antagonist isoxazolyl biphenylsulfonamide preparation pharmacokinetics.
In a previous report its was demonstrated that merging together key structural elements present in an AT1 receptor antagonist (irbesartan) with key structural elements in a biphenylsulfonamide ETA receptor antagonist followed by addnl. optimization provided a product which is a dual-action receptor antagonist (DARA), which potently blocked both AT1 and ETA receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT1 and ETA receptor potency of 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 (I). Efforts centered on modifying the 2′-side chain of I and examining the (isoxazolyl)sulfonamide moiety in I. This effort resulted in the discovery of 4′-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5-dimethyl-3-isoxazolyl)-2′-(ethoxymethyl)[1,1′-biphenyl]-2-sulfonamide (II) as a highly potent second-generation DARA. This compound also showed substantially improved pharmacokinetic properties compared to I. In rats, DARA II reduced blood pressure elevations caused by i.v. infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA I or AT1 or ETA receptor antagonists alone. II clearly demonstrated superiority over irbesartan (an AT1 receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT1 and ETA receptor blockade in a single mol. The crystal and mol. structures of II were reported.
Journal of Medicinal Chemistry published new progress about Angiotensin II receptor antagonists. 89003-95-2 belongs to class bromides-buliding-blocks, and the molecular formula is C8H4BrNO, Synthetic Route of 89003-95-2.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary