135689-65-5Relevant academic research and scientific papers
Synthesis and angiotensin II receptor antagonist activity of C-linked pyrimidine derivatives
Nicolai, E.,Cure, G.,Goyard, J.,Kirchner, M.,Teulon, J. M.,et al.
, p. 365 - 376 (2007/10/02)
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
N-3-Substituted Pyrimidones as Potent, Orally Active, AT1 Selective Angiotensin II Receptor Antagonists
Salimbeni, Aldo,Canevotti, Renato,Paleari, Fabio,Poma, Davide,Caliari, Saturnino,et al.
, p. 4806 - 4820 (2007/10/03)
A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared.Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes.The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration.Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SKandF 108566).According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency.Methyl 2-methyl>-1-(6H)-pyrimidinyl>methyl>-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action.It was selected for clinical evaluation in the treatment of hypertension in man.
Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists
Nicolai,Cure,Goyard,Kirchner,Teulon,Versigny,Cazes,Caussade,Virone-Oddos,Cloarec
, p. 2371 - 2386 (2007/10/02)
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.
