A potent, orally active, balanced affinity angiotensin II AT1 antagonist and AT2 binding inhibitor

Laszlo, Stephen E. de; Quagliato, Carol S.; Greenlee, William J.; Patchett, Arthur A.; Chang, Raymond S.L.; Lotti, Victor J.; Chen, Tsing Bau; Scheck, S.; Faust, Kristi A.

doi:10.1021/jm00073a024

Cited by 114 publications

(36 citation statements)

References 8 publications

(12 reference statements)

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“…Substituted quinazolone groups were previously successfully employed in programs aimed at making selective AT2R antagonists. [121][122][123][124][125][126][127] As a consequence of these findings, substituted quinazolinone groups were attached to the biaryl scaffold of 10 to replace the bicyclic imidazopyridine ring system, as exemplified by the most potent and AT2R…”

Section: (I) From the Methylene Imidazopyridine To Quinazolinonesmentioning

confidence: 99%

Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

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The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

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Section: (I) From the Methylene Imidazopyridine To Quinazolinonesmentioning

confidence: 99%

Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

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“…The target compounds of this contribution, the quinazolones are considered to be important heterocyclic substances with diverse biological and pharmacological activities depending on the position and properties of the ring substituents [16][17][18][19][20]. Recently, a set of novel imidazo[1,5-b]-quinazoline-1,5-diones (see Fig.…”

Section: Introductionmentioning

confidence: 99%

Liquid chromatographic enantiomer separations of novel quinazolone derivatives on quinine carbamate based chiral stationary phases using hydro-organic mobile phases

Gyimesi‐Forrás

Kökösi

Szabó

et al. 2004

Journal of Chromatography A

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“…12) was identified as a potent, orally active antagonist at AT 1 receptor. Stepwise structural modifications of the substituent on quinazolinone core during SAR studies which included compound 33 led to the discovery of the first potent balanced AT 1 /AT 2 antagonist L-159689 (34), displaying oral activity in rats [47].…”

Section: At 1 /At 2 Receptor Antagonistsmentioning

confidence: 99%

Multitarget Cardiovascular Drugs

Trstenjak¹,

Kikelj

2011

CMC

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Cardiovascular disease is the number one cause of death globally. Design of cardiovascular drugs based on new paradigms is therefore a prominent goal of medicinal chemistry. Designed multiple ligands, targeting two or more proteins involved in pathogenesis of disease have become a viable concept in drug discovery. Although adjustment of the activities ratio at the different targets is a demanding and challenging task, modulation of two or more targets involved in a cardiovascular disease may be more successful for therapeutic application than treatment directed against each target alone, because of improved pharmacodynamic and pharmacokinetic properties of designed multitarget drugs. The article reviews the applications of multitarget approach to cardiovascular drug design, covering angiotensin-converting enzyme/neutral endopeptidase inhibitors, neutrale endopeptidase/endothelin-converting enzyme inhibitors, angiotensin-converting enzyme/neutral endopeptidase/endothelin-converting enzyme inhibitors, dual angiotensin/endothelin receptor and angiotensin1/angotensin2 receptor antagonists and angiotensin receptor antagonist/neutral endopeptidase inhibitors.

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A potent, orally active, balanced affinity angiotensin II AT1 antagonist and AT2 binding inhibitor

Cited by 114 publications

References 8 publications

Small‐molecule AT2 receptor agonists

Small‐molecule AT2 receptor agonists

Liquid chromatographic enantiomer separations of novel quinazolone derivatives on quinine carbamate based chiral stationary phases using hydro-organic mobile phases

Multitarget Cardiovascular Drugs

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