An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

Aulakh, Gurpreet Kaur; Sodhi, Rupinder Kaur; Singh, Manjeet

doi:10.1016/j.lfs.2007.06.007

Cited by 75 publications

(73 citation statements)

References 203 publications

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“…Nonpeptide ARBs, such as candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and azilsartan, have been developed and successfully tested in hypertensive patients. [8][9][10] These agents commonly contain a biphenylmethyl moiety but have different side chains. 11,12) The aims of the present study were to characterize and compare the pharmacological properties of BR-A-657 with those of losartan by examining its antagonistic effects on human recombinant HEK-293 cell membranes, on the Ang II-induced contraction of rabbit aortic segments, and on Ang II-induced pressor response in rats, and to investigate its antihypertensive effects in furosemide-treated and renal hypertensive rats.…”

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confidence: 99%

Pharmacological Characterization of BR-A-657, a Highly Potent Nonpeptide Angiotensin II Receptor Antagonist

Lee

Kim

et al. 2013

Biological & Pharmaceutical Bulletin

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given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT 1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.Key words BR-A-657; losartan; AT 1 receptor; angiotensin II pressor; renal hypertensive rat Hypertension is important not only because of its prevalence but also because it is a major modifiable risk factor of associated cardiovascular and renal complications. 1) Current guidelines emphasize the importance of managing hypertension to reduce substantial morbidity and mortality associated with cardiovascular events. 2-4)The renin angiotensin system (RAS) plays a pivotal role in cardiovascular regulation by blood pressure and fluid-electrolyte balance control. Angiotensin II (Ang II) circulates in the blood stream and is the principal mediator of the RAS system, stimulates vasoconstriction and the retention of salt and water, releases aldosterone from the adrenal glands, and modulates central effects such as drinking.5) The haemodynamic and cardiovascular effects of Ang II are all mediated by its binding to receptors on the surfaces of target cells within central and peripheral blood vessels, and within the heart and other organs.6) There are two distinct receptor subtypes, namely, AT 1 and AT 2 , and AT 1 receptors are thought to mediate the major effects of Ang II in cardiovascular, renal, neuronal, endocrine, hepatic, and other target cells. Many studies have shown that Ang II produces its biological activities by stimulating AT 1 receptors, especially in its blood pressure regulatory effect. Therefore, an Ang II receptor blocker (ARB) that blocks AT 1 receptors is considered to provide potential therapeutic strategies for the managements of hypertension and cardiovascular and renal diseases, and to date, several nonpeptide AT 1 receptor antagonists have been developed for the treatment of hypertension and heart failure. 7,8)

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Pharmacological Characterization of BR-A-657, a Highly Potent Nonpeptide Angiotensin II Receptor Antagonist

Lee

Kim

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Losartan has been widely used to lower arterial BP and to prevent or attenuate the progression of renal disease. [12][13][14][15] Notably, the losartan binding site in AT1R does not overlap with the angiotensin binding site. 16,17 This study was performed on rat renal proximal tubule cells (RPTCs) in primary culture and on HEK 293a (HEK) cells, a cell line derived from human embryonic kidney.…”

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confidence: 99%

Binding of Losartan to Angiotensin AT1 Receptors Increases Dopamine D1 Receptor Activation

Liu

Scott

Crambert

et al. 2012

Journal of the American Society of Nephrology

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Signaling through both angiotensin AT1 receptors (AT1R) and dopamine D1 receptors (D1R) modulates renal sodium excretion and arterial BP. AT1R and D1R form heterodimers, but whether treatment with AT1R antagonists functionally modifies D1R via allosterism is unknown. In this study, the AT1R antagonist losartan strengthened the interaction between AT1R and D1R and increased expression of D1R on the plasma membrane in vitro. In rat proximal tubule cells that express endogenous AT1R and D1R, losartan increased cAMP generation. Losartan increased cAMP in HEK 293a cells transfected with both AT1R and D1R, but it did not increase cAMP in cells transfected with either receptor alone, suggesting that losartan induces D1R activation. Furthermore, losartan did not increase cAMP in HEK 293a cells expressing AT1R and mutant S397/S398A D1R, which disrupts the physical interaction between AT1R and D1R. In vivo, administration of a D1R antagonist significantly attenuated the antihypertensive effect of losartan in rats with renal hypertension. Taken together, these data imply that losartan might exert its antihypertensive effect both by inhibiting AT1R signaling and by enhancing D1R signaling. 23: 421-428, 201223: 421-428, . doi: 10.1681 Sodium excretion and renal vascular tonus are bidirectionally regulated by dopamine, acting on dopamine D1 receptors (D1R) and angiotensin II, acting on angiotensin AT1 receptors (AT1R). [1][2][3] Several lines of evidence suggest that AT1R and D1R form a heteromeric signaling complex. [4][5][6] We recently reported that activation of either AT1R or D1R might cause internalization and/or interruption of the signaling capacity of the other receptor. 6 These observations imply that AT1R and D1R may allosterically modulate each other. Several recent studies have shown that the G-protein coupled receptor (GPCR) often forms heteromers and it has been suggested that allosteric modification within such heteromers will fine-tune receptor signal strength and offer novel opportunities for therapeutic approaches. 7-10 Because AT1R antagonists are far more commonly used therapeutically than AT1R agonists, we decided to test whether losartan, an AT1R antagonist, 11 might influence AT1R and D1R interaction and modulate D1R signaling. Losartan has been widely used to lower arterial BP and to prevent or attenuate the progression of renal disease. [12][13][14][15] Notably, the losartan binding site in AT1R does not overlap with the angiotensin binding site. 16,17 This study was performed on rat renal proximal tubule cells (RPTCs) in primary culture and on HEK 293a (HEK) cells, a cell line derived from human embryonic kidney. The endogenous expressions of D1R and AT1R are relatively high in RPTCs 1,18 and low in HEK cells. Therefore, HEK cells were used for expression of fluorescently tagged receptors and J Am Soc Nephrol 421BASIC RESEARCH mutant receptors. We performed a series of biochemical studies, which indicated that losartan strengthens the interaction between AT1R and D1R and that losartan incr...

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“…The resulting solid was subsequently filtered and purified, giving the titled compound 12 (5 g, 50%). This was characterized as follows: HPLC purity: 97.59%; 1 …”

Section: Methyl 1-((2'-amidobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[dmentioning

confidence: 99%

“…Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme, and angiotensin II is the principal pressor agent of the rennin-angiotensin system [1,12], with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan Kamedoxomil blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of related substances of Azilsartan Kamedoxomil

Maddi

Garaga

Reddy

et al. 2017

Current Issues in Pharmacy and Medical Sciences

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Azilsartan Kamedoxomil is an AT1-subtype angiotensin II receptor blocker (ARB). During the laboratory synthesis of Azilsartan Kamedoxomil, four related substances of Azilsartan Kamedoxomil were observed and identified. These were 2-Ethoxy--(4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-methoxy-1H-benzimidazole-7-carboxylate (methoxy analogue of azilsartan medoxomil, 11), Methyl 1-((2'-amidobiphenyl-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (amide methyl ester, 12). The present work describes the origin, synthesis and characterization of these related substances.

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An update on non-peptide angiotensin receptor antagonists and related RAAS modulators

Cited by 75 publications

References 203 publications

Pharmacological Characterization of BR-A-657, a Highly Potent Nonpeptide Angiotensin II Receptor Antagonist

Pharmacological Characterization of BR-A-657, a Highly Potent Nonpeptide Angiotensin II Receptor Antagonist

Binding of Losartan to Angiotensin AT1 Receptors Increases Dopamine D1 Receptor Activation

Synthesis and characterization of related substances of Azilsartan Kamedoxomil

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