- DUAL-ACTING ANTIHYPERTENSIVE AGENTS
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In one aspect, the invention relates to compounds having the formula: wherein: Ar, r, Z, X, R3, and R5-7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.
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Page/Page column 39
(2010/02/17)
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- Synthesis and angiotensin II antagonist activity of novel 2-arylthio-3-(2-alkyl-1-(4-carboxybenzyl)imidazolyl)acrylic acids
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A series of 2-arylthio-3-(2-alkyl-1-(4-carboxybenzyl)imidazolyl)acrylic acids were synthesized and evaluated as angiotensin II antagonists on guinea-pig ileal smooth muscle. 2-Phenylthio-3-(2-n-butyl-1-(4-carboxybenzyl)imidazolyl) acrylic acid was found t
- Shafiee,Hadizadeh,Karimi,Mahmoudian,Razzaghi
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p. 535 - 538
(2007/10/03)
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- A New Regioselective Synthesis of 1,2,5-Trisubstituted 1H-Imidazoles and Its Application to the Development of Eprosartan
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A new method is presented for the preparation of 1,2-disubstitued-1H-imidazole-5-carboxaldehydes by the reaction of N-monosubstituted amidines with 2-halo-3-alkoxy-2-propenals. The reaction is highly regioselective with ratios of 1,2,5:1,2,4-imidazolecarboxaldehydes ranging from 85:15 to 100: 0. This methodology could be extended with similar results to the synthesis of imidazole-5-nitriles by the reaction of 2-bromo-3-methoxy-2-propenenitrile with N-monosubstituted amidines.
- Shilcrat, Susan C.,Mokhallalati, Mohamed K.,Fortunak, Joseph M. D.,Pridgen, Lendon N.
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p. 8449 - 8454
(2007/10/03)
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- Syntheses of substituted-pyrrolo[2,3-d]imidazoles and substituted-pyrrolo[3,2-d]imidazoles
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Starting from the readily available 2-alkyl-4-formylimidazole substituted-pyrrolo[2,3-d]imidazoles and substituted-pyrrolo[3,2-d]imidazoles have been prepared.
- Shafiee, A.,Hadizadeh, F.,Foroumadi, A.
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p. 813 - 815
(2007/10/03)
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- Potent Nonpeptide Angiotensin II Receptor Antagonists. 2. (1-Carboxybenzyl)imidazole-5-acrylic Acids
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The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J.Med.Chem. 1992, 35, 3858).Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr4 residue of angiotensin II.Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity.SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency.Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented.The parent diacid analog, SKF 108566 or (E)-3--2-propenoic acid, is currently in clinical development for the treatment of hypertension.
- Keenan, Richard M.,Weinstock, Joseph,Finkelstein, Joseph A.,Franz, Robert G.,Gaitanopoulos, Dimitri E.,et al.
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p. 1880 - 1892
(2007/10/02)
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