Pharmacology of SC-52458, an Orally Active, Nonpeptide Angiotensin AT1 Receptor Antagonist

Olins, Gillian M.; Corpus, Valerie M.; Chen, Susan T.; McMahon, Ellen G.; Palomo, Maria A.; McGraw, Dean E.; Smits, Glenn J.; Null, Christopher L.; Brown, Melanie A.; Bittner, Steven E.; Koepke, J P; Blehm, Delores J.; Schuh, Joseph R.; Baierl, Chris J.; Schmidt, Ronald; Cook, Chyung S.; Reitz, David B.; Penick, Mark A.; Manning, Robert E.; Blaine, Edward H.

doi:10.1097/00005344-199310000-00016

Cited by 27 publications

(9 citation statements)

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“…This finding is also consistent with the findings of an in vitro functional study showing that the Ang II-induced depolarization of the rat superior cervical ganglion was blocked by losartan, but not by PD-123177 (24). In the present in vivo experiment, the ganglionic stimulatory response to Ang II in the dog cardiac sympathetic ganglia was also inhibited by forasartan, which is described as a non-peptide competitive AT1-receptor antagonist (25), but not by PD-123319, an AT2-receptor antagonist. Therefore, the Ang II-induced stimulation of the dog sympathetic ganglia is also mediated by the AT1 subtype of the Ang II receptor.…”

Section: +supporting

confidence: 92%

Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

Tokunaga

Kushiku

Yamada

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the ganglionic effects of angiotensin II (Ang II) and the signal transduction involved in the cardiac sympathetic ganglia by the direct administration of agents to the ganglia through the right subclavian artery and monitoring the heart rate as an indicator of the ganglionic function in pithed dogs. Ang II given i.a. caused increases in the heart rate, which was inhibited by the treatment with the AT1-receptor antagonist forasartan, but not by the AT 2-receptor antagonist PD-123319. The stimulation by Ang II, but not by acetylcholine, was inhibited after treatment with an inhibitor of phospholipase C, U-73122; a cellpermeant modulator of the Ins(1,4,5)P3 receptors, 2-aminoethoxydiphenyl borate; an intracellular calcium and calcium-associated protein kinase inhibitor, HA-1077; calmodulin (CaM) inhibitor, W-7; Ca 2+ /CaMdependent protein kinase II inhibitor, KN-93; a selective protein kinase C inhibitor, calphostin C; and Na + -H + exchange inhibitor, dimethylamiloride. These results suggest that Ang II stimulates the ganglionic transmission at postsynaptic sites via the activation of AT1 receptor coupled to either activation of phospholipase C, phosphoinositide hydrolysis and subsequent increase in intracellular Ca 2+ and activation of protein kinase C and Ca 2+/ CaM kinase II, although this ganglionic stimulation seems to involve, at least in part, the protein kinases-dependent increase of amiloride-sensitive Na + inflow.

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Section: +supporting

confidence: 92%

Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

Tokunaga

Kushiku

Yamada

et al. 2001

Japanese Journal of Pharmacology

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“…The introduction of losartan as the first high-affinity, non-peptide, competitive antagonist with selectivity for A111 receptors has stimulated an extensive research into analogues (Timmermans et al 1993). Compounds such as L-158809 , SR 47436 (Cazaubon et al 1993), SC-52458 (Olins et al 1993), TCV-116 (Inada et al 1994) and ABBOTT-81988 (Lee et al 1994) were more potent than losartan or its metabolite, EXP 3174, and showed promising oral activity. These compounds inhibited AII-induced pressor responses in normotensive rats (Cazaubon et al 1993) and produced long-lasting decreases in blood pressure with minor changes in heart rate in spontaneously hypertensive rats (Olins et al 1993;Inada et al 1994) tensin I1 receptor antagonists did not change blood pressure in DOCA-salt hypertensive rats (Inada et al 1994).…”

Section: Therapeutic Roles Of Selective Angiotensin I1 Receptor Antagmentioning

confidence: 99%

“…These compounds inhibited AII-induced pressor responses in normotensive rats (Cazaubon et al 1993) and produced long-lasting decreases in blood pressure with minor changes in heart rate in spontaneously hypertensive rats (Olins et al 1993;Inada et al 1994) tensin I1 receptor antagonists did not change blood pressure in DOCA-salt hypertensive rats (Inada et al 1994). The antihypertensive responses were additive to ACE inhibitors (Lee et al 1994).…”

Section: Therapeutic Roles Of Selective Angiotensin I1 Receptor Antagmentioning

confidence: 99%

Angiotensin Receptors in Cardiovascular Diseases

Brown

Sernia

1994

Clin Exp Pharma Physio

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1. Angiotensin II (AII) plays a major role in cardiovascular function via direct actions on the vasculature, kidney, adrenal, heart, brain and sympathetic nerves. The cellular effects of AII are extensive and encompass hypertrophy, hyperplasia and the deposition of extracellular matrix. 2. The actions of AII are mediated by the AT1 and AT2 membrane receptor subtypes, and additional forms of each subtype. Evidence is emerging that selective changes in AII receptor subtypes occur in cardiovascular diseases. 3. Thyroid dysfunction increased cardiac, liver and kidney AII receptor density but decreased adrenal gland receptor density. In the heart, there was a selective increase in AT2 receptor density. 4. Diabetes increased cardiac, liver and adrenal gland AII receptor densities but decreased kidney receptor density. 5. Hypertension increased AII receptor density in the heart and kidney. A corresponding increase in receptor mRNA was prevented by selective AT1 receptor antagonists. 6. The human heart contained AII receptors in all chambers; right atrial receptor density was increased in coronary artery bypass graft patients. 7. The presence of AII receptor changes in these models of cardiac hypertrophy and hypertension raises the possibility of using orally active, subtype-selective agonists and antagonists to treat particular forms of cardiovascular diseases.

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“…Conformational analysis, using the molecular mechanics MM2 method, was carried out for each molecule to obtain the conformational minima within 8 kcal/mol of the global minimum. These minima (about 9000 conformers) were described by 10 interatomic distances that define the relative spatial disposition of five relevant functional groups belonging to all the molecules. A structure-activity relationship between the 3D molecular descriptors and the biological data was then assessed by chemometric techniques; cluster analysis was applied to reduce the large number of conformational minima found for each molecule.…”

Section: Molecular Modelingmentioning

confidence: 99%

Nonpeptide Angiotensin II Receptor Antagonists. Synthesis, in vitro Activity, and Molecular Modeling Studies of N-[(Heterobiaryl)methyl]imidazoles

Salimbeni

Canevotti²,

Paleari³

et al. 1994

J. Med. Chem.

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With the aim of explaining the influence of the structural changes on the biphenylic moiety on the activity, a series of N-[(heterobiaryl)methyl]imidazoles (I), constructed on the model of DuPont compounds by replacing either the central or terminal phenyl ring with a heteroaromatic one, such as furan, thiophene, thiazole, and pyridine, was synthesized. Compared to the reference DuPont compound (EXP-7711), all the heterobiaryl derivatives showed a reduced potency both in receptor binding (rat adrenal capsular membranes) and in the functional assay (angiotensin II-induced contraction of rabbit aorta strips). The lower activity was justified by the extensive molecular modeling studies, which took into consideration the conformational and electrostatic features of several heterobiaryl derivatives. On the basis of the results obtained, it was hypothesized that the central aromatic ring of the biarylic portion works as a spacer, orienting in the right way the terminal phenyl ring, whose electronic distribution is, instead, crucial to its fitting well with a lipophilic pocket at the receptor site.

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Pharmacology of SC-52458, an Orally Active, Nonpeptide Angiotensin AT1 Receptor Antagonist

Cited by 27 publications

References 0 publications

Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

Possible Involvement of Calcium-Calmodulin Pathways in the Positive Chronotropic Response to Angiotensin II on the Canine Cardiac Sympathetic Ganglia

Angiotensin Receptors in Cardiovascular Diseases

Nonpeptide Angiotensin II Receptor Antagonists. Synthesis, in vitro Activity, and Molecular Modeling Studies of N-[(Heterobiaryl)methyl]imidazoles

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