- New process for the synthesis of UP 269-6, a 1,2,4-triazolo[1,5-c]pyrimidine derivative as a potent orally active angiotensin II antagonist
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A new synthetic route to prepare the 2-hydroxy-5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]m ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine (UP 269-6, Ripisartan) is described. UP 269-6 is a non-peptide angiotensin II antagonist currently in phase
- Boyer,Fournel,Nicolai,Teulon
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p. 1307 - 1311
(2007/10/03)
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- Synthesis and angiotensin II receptor antagonist activity of C-linked pyrimidine derivatives
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The synthesis and pharmacological activity of nonpeptide angiotensin II (Ang II) receptor antagonists are presented.These 3-N-substituted pyrimidine 4(3H)-one and 4-O,N,S-substituted pyrimidine derivatives represent a series of C-linked biphenyl tetrazole
- Nicolai, E.,Cure, G.,Goyard, J.,Kirchner, M.,Teulon, J. M.,et al.
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p. 365 - 376
(2007/10/02)
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- Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists
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The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5- c]pyrimidine and 1,2,4-triazolo[4,3-c]-pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8- [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c] series. UP 269-6 (5- methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-[1,2,4]- triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 ± 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (K(i) AT1 = 24 nM; K(i) AT2 = 79 200 nM). This compound is currently undergoing extensive pharmacological and clinical development.
- Nicolai,Cure,Goyard,Kirchner,Teulon,Versigny,Cazes,Caussade,Virone-Oddos,Cloarec
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p. 2371 - 2386
(2007/10/02)
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