Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series

Bühlmayer, Peter; Furet, Pascal; Criscione, Leoluca; Gasparo, Marc de; Whitebread, Steven; Schmidlin, Tibur; Lattmann, René; Wood, Jeanette M.

doi:10.1016/s0960-894x(01)81117-3

Cited by 102 publications

(58 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AZL was synthesized in Takeda Pharmaceutical Company Limited (Osaka, Japan). Olmesartan (Yanagisawa et al, 1996), telmisartan (Ries et al, 1993), valsartan (Bü hlmayer et al, 1994), and irbesartan (Bernhart et al, 1993) were used in this experiment as competitors. Olmesartan was prepared from olmesartan medoxomil (Daiichi-Sankyo, Tokyo, Japan).…”

Section: Downloaded Frommentioning

confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

139

115

View full text Add to dashboard Cite

The angiotensin II (AII) antagonistic action of azilsartan (AZL) [2-ethoxy-1-{[2Ј-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid] was investigated in radioligand binding and function studies. AZL inhibited the specific binding of 125 I-Sar 1 -Ile 8 -AII to human angiotensin type 1 receptors with an IC 50 of 2.6 nM. The inhibitory effect of AZL persisted after washout of the free compound (IC 50 value of 7.4 nM). Olmesartan, telmisartan, valsartan, and irbesartan also inhibited the specific binding with IC 50 values of 6.7, 5.1, 44.9, and 15.8 nM, respectively. However, their inhibitory effects were markedly attenuated with washout (IC 50 values of 242.5, 191.6, Ͼ10,000, and Ͼ10,000 nM). AZL also inhibited the accumulation of AII-induced inositol 1-phosphate (IP1) in the cell-based assay with an IC 50 value of 9.2 nmol; this effect was resistant to washout (IC 50 value of 81.3 nM). Olmesartan and valsartan inhibited IP1 accumulation with IC 50 values of 12.2 and 59.8 nM, respectively. The activities of these compounds were markedly reduced after washout (IC 50 value of 908.5 and 22,664.4 nM). AZL was defined as an inverse agonist in an experiment by using a constitutively active mutant of human angiotensin type 1 receptors. In isolated rabbit aortic strips, AZL reduced the maximal contractile response to AII with a pDЈ 2 value of 9.9. The inhibitory effects of AZL on contractile responses induced by AII persisted after the strips were washed; these inhibitory effects were more potent than those of olmesartan. These results suggest that AZL is a highly potent and slowly dissociating AII receptor blocker. Its tight receptor binding might be expected to produce potent and long-lasting antihypertensive effects in preclinical and clinical settings.

show abstract

Section: Downloaded Frommentioning

confidence: 99%

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Ojima¹,

Igata²,

Tanaka³

et al. 2010

J Pharmacol Exp Ther

139

115

View full text Add to dashboard Cite

show abstract

“…1 One of the common ways of treatment of hypertension is to prevent the progression of target organ damage by controlling blood pressure, as stated in guidelines recently published in the sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. 2,3 The angiotensin II receptor antagonists are highly affective antihypertensive agents with excellent tolerability profiles.…”

Section: Valsartan (1) (S)-n-valeryl-n-((2mentioning

confidence: 99%

Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds

Zhang

Jiang

et al. 2007

Magnetic Reson in Chemistry

View full text Add to dashboard Cite

Valsartan (1), an antihypertensive drug of the sartan family, and three related compounds, 3-methyl-2-((2'-(1-methyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl) pentanoylamino)butyric acid (2), 3-isopropyl-6-propyl-4-(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl) morpholine-2,5-dione (3), and 3-isopropyl-6-propyl-4-(4'-(1H-tetrazol-5-yl)biphenyl4-ylmethyl) morpholine-2,5-dione (4), were studied by nuclear magnetic resonance (NMR) spectroscopy. Assignment of (1)H and (13)C NMR resonances for the compounds were completed using COSY, HSQC and HMBC techniques. It was found that each of the compounds 1, 2, and 4 had two sets of (1)H and (13)C resonances, suggesting the presence of two conformers in solution. Based on NOESY experiments at different temperatures, thermodynamic parameters of the conformational exchange process were deduced for these compounds. The exchange barrier was found to be 17.9 +/- 0.7, 18.5 +/- 0.8, and 17.7 +/- 0.6 kcal mol(-1) with the corresponding free energy difference (DeltaG) of 0.32 +/- 0.04, 0.23 +/- 0.01, and 0.13 +/- 0.04 kcal mol(-1) for 1, 2, and 4, respectively, at 298 K. Two conformations of valsartan were elucidated by NMR spectroscopy and quantum chemistry calculation. The results showed that two conformers of valsartan interchange via rotation about the C(O)--N bond.

show abstract

“…For the practical application of Pd catalysts, a valsartan precursor, which is known as a potent angiotensin II receptor antagonist, [22] was synthesized using the most electron-rich palladated oxime resin (4c). As the synthesis of valsartan requires aryl-aryl bond formation, which is a key step in the synthesis of valsartan, [23] a precursor of valsartan (6) was synthesized via the Suzuki coupling reaction of 2-bromobenzonitrile with arylboronate (5) at 508C for 2 h (Scheme 2).…”

Section: Suzuki Coupling Reaction Catalyzed By Palladated Oxime Resinsmentioning

confidence: 99%

Polymer‐Supported Electron‐Rich Oxime Palladacycle as an Efficient Heterogeneous Catalyst for the Suzuki Coupling Reaction

et al. 2014

View full text Add to dashboard Cite

Various electron-rich oxime palladacycle resins designed as heterogeneous catalysts were employed for the Suzuki coupling reaction of aryl halides with arylboronic acids. The electron-richness of the oxime ligand was controlled by the substituted alkoxy groups. Evaluation based on the electronic effect of the catalysts revealed that the alkoxy-substituted oxime palladacycle resins showed better catalytic activity than palladated Kaiser oxime resin in the Suzuki coupling reactions and that the catalytic activity of oxime palladacycle resins increased as the electron-richness of oxime ligand increased. The most electron-rich oxime palladacycle resin exhibited an excellent catalytic performance for the synthesis of both biaryl and heterobiaryl compounds, despite its heterogeneous system. As a practical application of the catalyst, a valsartan precursor was synthesized in high yield under mild conditions. The electronrich oxime resin could also be reused for up to 5 cycles while maintaining good catalytic activity in the Suzuki coupling reaction.

show abstract

Valsartan, a potent, orally active angiotensin II antagonist developed from the structurally new amino acid series

Cited by 102 publications

References 12 publications

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

In Vitro Antagonistic Properties of a New Angiotensin Type 1 Receptor Blocker, Azilsartan, in Receptor Binding and Function Studies

Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds

Polymer‐Supported Electron‐Rich Oxime Palladacycle as an Efficient Heterogeneous Catalyst for the Suzuki Coupling Reaction

Contact Info

Product

Resources

About