- N-substituted-1, 2, 4-triazolone compounds for treatment of cardiovascular disorders
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A class of N-substituted-1,2,4-triazolone compounds is described for use in treatment of cardiovascular disorders. Compounds of particular interest are angiotensin II antagonists of the formula wherein R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 4-methylbutyl, n-pentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl and hydroxyalkyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neo-pentyl, propylthio and butylthio; wherein each of R3 through R11 is hydrido with the proviso that at least one of R5 and R9 must be selected from COOH, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R42 and R43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl. These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.
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- SUBSTITUTED 1,2,4-TRIAZOLES BEARING ACIDIC FUNCTIONAL GROUPS AS ANGIOTENSIN II ANTAGONISTS
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Novel substituted triazolinone, triazolinethione, and triazolinimine compounds of the formula I are useful as angiotensin II antagonists. STR1
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- SUBSTITUTED TRIAZOLES AS ANGIOTENSIN II ANTAGONISTS
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Novel substituted triazoles of the formula (I), which are useful as angiotensin II antagonists, are disclosed. STR1
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- Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4]triazoles
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By a variety of synthetic routes, we have synthesized a series of 3,4,5- trisubstituted 4H-1,2,4-triazoles and a related series of 3H-imidazo[1,2- b][1,2,4]triazoles and evaluated them in vitro and in vivo as angiotensin II (AII) antagonists. Principal efforts focused on triazoles bearing an n-alkyl substituent at C3 and a 4-[(2-carboxybenzoyl)amino]benzyl, (2'- carboxybiphenyl-4-yl)methyl, or [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl side chain at N4. Among numerous variations at C5, benzylthio groups gave the best potency. Particularly noteworthy was 3-n-butyl-5-[(2- carboxybenzyl)thio]-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-4H-1,2,4- triazole (71, IC50 1.4 nM), which blocked the AII pressor response in conscious rats at 0.3 mg/kg iv with a duration of action of approximately 6 h, similar to that of DuP 753. Although 71 was active orally only at a 10- fold higher dose level, good oral bioavailability was demonstrated for a monoacidic analogue 62. Most potent among the bicyclic derivatives was 2-n- butyl-5,6-dimethyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H- imidazo[1,2-b][1,2,4]triazole (93, IC50 7.8 nM). The effects of hydrophobic, hydrogen-bonding, and ionic interactions with the AT1 receptor are considered.
- Ashton,Cantone,Chang,Hutchins,Strelitz,MacCoss,Chang,Lotti,Faust,Chen,Bunting,Schorn,Kivlighn,Siegl
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p. 591 - 609
(2007/10/02)
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- Acyl amidine and acyl, guanidine substituted biphenyl derivatives
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Novel compounds are disclosed having the formula STR1 and wherein R1, R2 and R3 are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.
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- Angiotensin II receptor antagonists
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Compounds are disclosed having the formula: STR1 The compounds of the invention are angiotensin II receptor antagonists.
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- Synthesis and Structure-Activity Relationships of Nonpeptide, Potent Triazolone-Based Angiotensin II Receptor Antagonists
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2,5-Dibutyl-2,4-dihydro-4--4'-yl>methyl>-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action.To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbitaortic rings.It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities.Acidic groups generally result in a slight decrease in binding affinity.Branched chains are unfavorable.The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding.The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.
- Huang, Horng-Chih,Reitz, David B.,Chamberlain, Timothy S.,Olins, Gillian M.,Corpus. Valerie M.,et al.
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p. 2172 - 2181
(2007/10/02)
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- A New Series of Imidazolones: Highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists
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Starting from the structure of the novel nonpeptide AT1 receptor antagonists DuP 753 (losartan), a new series of potent antagonists was designed.In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure.The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5.Like the imidazole series, the best substituents were the linear butyl chain in position 2 and the methyl group in position 3.Antagonistic activity was assessed by the ability of the compounds to competively inhibit AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings.The most active compounds had IC50 values in the nanomolar range.In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally.Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally.This molecule is now undergoing clinical trials for the treatment of hypertension.
- Bernhart, Claude A.,Perreaut, Pierre M.,Ferrari, Bernard P.,Muneaux, Yvette A.,Assens, Jean-Louis A.,et al.
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p. 3371 - 3380
(2007/10/02)
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