Gloria J. Zingaro

Potent imidazole angiotensinII antagonists: acyl sulfonamides and acyl sulfamides as tetrazole replacements

Abstract Acyl sulfonamides and acyl sulfamides were synthesized and their in vitro and in vivo biological properties evaluated. AT1 binding affinities for these potent AII antagonists were similar to their tetrazole analogs. An enhancement in AT2 potencies was observed, particularly with acyl sulfonamides or sulfamides bearing hydrophobic substituents.

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

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 AT 1 and AT 2 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.

Quinazolinones 2: QSAR and in vivo characterization of AT1 selective AII antagonists

Abstract The structure activity relatoionship, linear regression analysis and in vivo evaluation of a series of substituted 2-butyl-3-[(2′-tetrazol-5-yl)biphen-4-yl)methyl]quinazolin-4(1H)-ones as antagonists of the AT1 receptor for angiotensin II is presented. L-159,093 (2-butyl-6-(N-isopropyl-N-methyl-carbamoyl)amino-3-[(2′-tetrazol-5-yl)biphen-4-yl)methyl]quin azolin-4(1H)-one (IC50=0.1nM rabbit aorta) is shown to be a potent orally active AII antagonist in rats and rhesus.

The SAR of 6-(N-alkyl-N-acyl)-2-propyl-3-[(2′-tetrazol-5-yl)biphen-4-yl)methyl]-quinazolinones as balanced affinity antagonists of the human AT1 and AT2 receptors

Abstract Modification of the 6-N-alkyl-N-acyl groups of L-159,689, 6 6-(N-benzoyl-N-pentyl)-amino-2-propyl-3-[(2′-(tetrazol-5-yl)biphen-4-yl)methyl]quinazolin-4-(3H)one led to the identification of the 6-(N-benzoyl-N-(3-pyridylmethyl)) analog (L-162,537). L-162,537 had improved aqueous solubility and oral bioavailability in the dog. The SAR of this class of AT1 and AT2 ligands is discussed.

Quinazolinone biphenyl acylsulfonamides: a potent new class of angiotensin-II receptor antagonists

Abstract A new series of quinazolinone-based AT 1 selective antagonists, bearing acylsulfonamides (-SO 2 NHCOR) as the tetrazole bioisosteres, was evaluated. While AT 1 potencies remained similar to the tetrazole analogs, the AT 2 receptor affinities were significantly improved with the introduction of acylsulfonamide groups. Several of these antagonists displayed improved in vivo properties.

Development of angiotensin II antagonists with equipotent affinity for human AT1 and AT2 receptor subtypes.

Abstract The quinazoline sulfonylcarbamate L-163,579 (9) is a potent, balanced antagonist of the binding of angiotensin II (Ang II) to human AT 1 and AT 2 receptors. This antagonist produces a long-lasting blockade of Ang II-induced pressor response in both rats and dogs after oral administration.

In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for angiotensin AT2 receptors

Abstract L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[(2′-(N-(3-methyl-1-butoxy)carbonylaminosulfonyl)[1,1′]-biphenyl-4-yl]-methyl]-3H-imidazo-[4,5-b] is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.

AT1 selective angiotensin II antagonists with phenoxyphenylacetic acid as a biphenyl replacement part I

Abstract A series of nonpeptidic AT1 selective angiotensin II (AII) antagonists containing a phenoxyphenylacetic acid element as a biphenyl tetrazole replacement have been identified. This series yielded compound 20 which exhibited binding affinities of AT1 = 16 nM; AT2 = 22 μM and demonstrated modest in vivo duration in blockade of AII pressor response in conscious rats after either i.v. or p.o. administration.

α-Phenoxyphenylacetic acid derived angiotensin II antagonists with low nanomolar AT1/AT2 receptor subtype affinity (Part II)

Abstract Directed synthesis and pharmacological evaluation in a recently described class of α-phenoxyphenylacetic acid bearing angiotensin II (AII) receptor antagonists has afforded further potent AT 1 -selective AII antagonists. Substitution in the central aromatic ring significantly increases AT 2 receptor affinity such that the n -propyl derivative 7g displayed low nanomolar potency at both AT 1 and AT 2 receptor subtypes.

Triazolinones as nonpeptide angiotensin II antagonists. 2. discovery of a potent and orally active triazolinone acylsulfonamide

Abstract A series of trisubstituted triazolinones with a [2′-(N-acylsulfamoy)biphenyl-4-yl]methyl side chain at N4 has been prepared. The inhibition of AII pressor responses by these potent AT1-selective AII antagonists indicated some of them to be superior in vivo to their tetrazole counterparts. At 1 mg/kg, 3d (L-159,913) was effective orally with > 4 h duration in dogs and had significant efficacy with > 10 h duration i.v. in chimpanzees.