Non-peptide angiotensin II receptor antagonists. 2. Design, synthesis, and biological activity of N-substituted (phenylamino)phenylacetic acids and acyl sulfonamides.
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 microM), 9d (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.49 microM), and 9e (AT1 IC50 = 5.3 nM, AT2 IC50 = 0.56 microM) 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 microM), 16b (AT1 IC50 = 1 nM, AT2 IC50 = 2.9 microM), and 16c (AT1 IC50 = 0.8 nM, AT2 IC50 = 0.42 microM) 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 microM of 9c vs 0.2 microM 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
D S
DS
Merck Research Laboratories, Rahway, New Jersey 07065.
Bagley
S W
SW
Chang
R S
RS
Lotti
V J
VJ
Chen
T B
TB
Kivlighn
S D
SD
Zingaro
G J
GJ
Siegl
P K
PK
Patchett
A A
AA
Greenlee
W J
WJ
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008636:Mesencephalon / Q000378:metabolism; D015394:Molecular Structure; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013777:Tetrazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D010648:Phenylacetates; D011725:Pyridines; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D013777:Tetrazoles; C085081:3-((4-(N-(((phenylsulfonyl)carbamoyl)phenylmethyl)-N-ethylamino)phenyl)methyl)-5,7-dimethyl-2-ethyl-3H-imidazo(4,5-b)pyridine; D015059:1-Sarcosine-8-Isoleucine Angiotensin II