Dual Angiotensin II and Endothelin A Receptor Antagonists: Synthesis of 2‘-Substituted N-3-Isoxazolyl Biphenylsulfonamides with Improved Potency and Pharmacokinetics

In a previous report we demonstrated that merging together key structural elements present in an AT1 receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ETA receptor antagonist (2) followed by additional optimization provided compound 3 (Figure 1) as 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 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 (Figure 1) 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 AT1 or ETA receptor antagonists alone....