Pyrido[2,3-d]pyrimidine Angiotensin II Antagonists

Abstract

A series of pyrido[2,3-d]pyrimidine angiotensin II (A II) antagonists was synthesized and tested for antagonism of A II. Compounds with a biphenylyltetrazole pharmacophore and small alkyl groups at the 2- and 4-positions of the pyridopyrimidine ring were found to be the most potent in an AT1 receptor binding assay and in blocking the A II pressor response in anesthetized, ganglion-blocked A II-infused rats. 5,8-Dihydro-2,4-dimethyl-8-[(2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl)methyl]pyrido[2,3-d]pyrimidin-7(6H)-one (4a) was one of the more potent compounds in the binding assay and was the most efficacious compound in the A II-infused rat model. Further study of 4a in Goldblatt (2K-1C) rats showed the compound to have oral bioavailability and to be an efficacious and potent compound in a high renin form of hypertension.

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

“…[36,76] In summary, the combinations of substituents apparently more widely explored in literature for both structures are a) In 14.08% of the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11): G 2 = nitrogen substituent, G 4 = oxygen substituent (in particular as a carbonyl group), R 5 = phenyl group, R 6 Thus, in the case of the structures 11 (C5-C6 single bond), 53.12% present at least a substituent at C5 and a CH2 at C6 (in most of them a carbon substituent [29,30] and, more precisely, a phenyl ring in one half of the structures [50,51]) while only 3.19% present a substituent at C6 and a CH2 at C5 (in this case most structures present a carbon substituent [52,53] which is a phenyl ring in also one half of them [31,42]). Finally, 20.86% of the structures do not present substituents at C5 or C6 [20,54]. These three substitution patterns cover 84.87% of the total diversity.…”

Predicting 3H-1,2,4-triazolinones as angiotensin II receptor antagonists: 2D and 3D QSAR by kNN-molecular field analysis approach

“…The pioneering efforts of the DuPont Group have generated a promising first non-peptide AT 1 antagonist losartan, which represent the prototype of the sartans. In the last decades several selective antagonists have been designed developed and are used to treat both hypertension and damage associated with the diseases such as arthrosclerosis and diabetes (Bernhart et al, 1993;Buhl Mayer et al, 1994;Ellingboe et al, 1994;Judd et al, 1994;Keenan et al, 1993;Kubo et al, 1993;Middlemiss et al, 1991;Ries et al, 1993;Salimbeni et al, 1995;Wong et al, 1990;Yanagisawa et al, 1996).…”

Angiotensin II Receptor Antagonists: An Emerging New Class of Cardiovascular Therapeutics.

“…An example is the AT1 receptor antagonist tasosartan (Fig. 2) (16). The enol metabolite, enoltasosartan, i s responsible for the long pharmacodynamic action of the drug (17).…”