- Non-Peptide Angiotensin II Receptor Antagonists. 2. Design, Synthesis, and Biological Activity of N-Substituted (Phenylamino)phenylacetic Acids and Acyl Sulfonamides
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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.
- Dhanoa, Daljit S.,Bagley, Scott W.,Chang, Raymond S. L.,Lotti, Victor J.,Chen, Tsing-Bau,et al.
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p. 4239 - 4249
(2007/10/02)
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