A new class of balanced AT1/AT2 angiotensin II antagonists: quinazolinone AII antagonists with acylsulfonamide and sulfonylcarbamate acidic functionalities

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Abstract

The structure activity relationships of a series of 2-alkyl-6-(acylamino)-3-[((2′-acylaminosulfonyl)biphenyl-4-yl)methyl]quinazolin-4-(3H)-ones were studied in order to identify balanced angiotensin II antagonists capable of potent binding to both AT1 and AT2 angiotensin receptor subtypes. The optimization of the substitution pattern led to the discovery of a potent, balanced quinazolinone antagonist L-162,393, which displayed long lasting blockade of angiotensin pressor response in rats, dogs and rhesus monkeys.

The development of a series of potent quinazilinone derived angiotensin II antagonists capable of inhibition of AII binding to both AT1 and AT2 receptor subtypes is described. L-162,393 (R1=CON(Me)i-Pr, R2=H, R3=Bu, R4=CO2CH2CH2CHMe2) was shown to inhibit the the AII induced pressor response when dosed orally to rats dogs and monkeys.

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    Moreover compound L-162, 393 blocking AI1 pressor response in rats (1 mg/kg, i. v. or p. o.) with duration of action exceeding 6 h. This antagonist was superior to other quinazolinones when administered orally to dogs, and also showed oral activity in rhesus monkeys [165]. The result of quinazolinone biphenyl acylsulfonamides 211 (Fig. 40) clearly indicated that, with similar AT1 receptor binding affinities acylsulfonamides are potent AII antagonists than corresponding tetrazole derivatives.

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