Non-Peptide Angiotensin II Receptor Antagonists. 2. Design, Synthesis, and Biological Activity of N-Substituted (Phenylamino)phenylacetic Acids and Acyl Sulfonamides

Article abstract of DOI:10.1021/jm00078a014

The design, synthesis, and biological activity of a new class of highly potent non-peptide AII receptor antagonists derived from N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides which exhibit a high selectivity for the AT₁ receptor are described.A series of N-substituted (phenylamino)phenylacetic acids (9) and acyl sulfonamides (16) and a tetrazole derivative (19) were synthesized and evaluated in the in vitro AT₁ (rabbit aorta) and AT₂ (rat midbrain) binding assay.The (phenylamino)phenylacetic acids 9c (AT₁ IC₅₀=4 nM, AT₂ IC₅₀=0.74 μM), 9d (AT₁ IC₅₀=5.3 nM, AT₂ IC₅₀=0.49 μM), and 9e (AT₁ IC₅₀=5.3 nM, AT₂ IC₅₀=0.56 μM) were found to be the most potent AT₁-selective AII antagonists in the acid series.Incorporation of various substituents in the central and bottom phenyl rings led to a decrease in the AT₁ and AT₂ binding affinity of the resulting compounds.Replacement of the carboxylic acid (CO2H) in 9c, 9d, and 9e with the bioisostere acyl sulfonamide (CONHSO2Ph) resulted in a (5-7)-fold increase in the AT₁ potency of 16a (AT₁ IC₅₀=0.9 nM, AT₂ IC₅₀=0.2 μM), 16b (AT₁ IC₅₀=1 nM, AT₂ IC₅₀=2.9 μM), and 16c (AT₁ IC₅₀=0.8 nM, AT₂ IC₅₀=0.42 μM) and yielded acyl sulfonamides with subnanomolar AT₁ activity.Incorporation of the acyl sulfonamide (CONHSO2Ph) for the CO2H of 9c not only enhanced the AT₁ potency but also effected a marked increase in the AT₂ potency of 16a (AT₂ IC₅₀=0.74 μM of 9c vs 0.2 μM of 16a) and made it the most potent AT₂ antagonist in this study.Replacement of the CO2H of 9b with the bioisostere tetrazole resulted in 19 (AT₁ IC₅₀=15 nM) with a 2-fold loss in the AT₁ and a complete loss in the AT₂ binding affinity. (Phenylamino)phenylacetic acid 9c demonstrated good oral activity in AII-infused conscious normotensive rats at an oral dose of 1.0 mg/kg by inhibiting the pressor response for >6 h.Acyl sulfonamides 16a-c displayed excellent in vivo activity by blocking the AII-induced pressor response for >6 h after oral administration in conscious rats at a 3.0 mg/kg dose level.Both acyl sulfonamides 16a and 16c exhibited superior in vivo activity in rats compared to that of (phenylamino)phenylacetic acid 9c.