Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Arulprakasajothi, M.; Wan, Yiqian; Murugaiah, A. M. S.; Wallinder, Charlotta; Wu, Xiongyu; Plouffe, Bianca; Botros, Milad; Nyberg, Fred; Hallberg, Anders; Gallo‐Payet, Nicole

doi:10.1016/j.bmc.2010.03.064

Cited by 26 publications

(22 citation statements)

References 31 publications

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“…A CYP inhibition of 33% (2B6), 24% (2C9), 25% (2C19), 5% (2E1), 28% (3A4), and 25% (3A5) was observed at a 10 μM concentration of 60 . The oxo‐pyrrolodin 60 acts as an AT2R agonist and induced neurite outgrowth in the NG108‐15 cell assay, an effect that was abolished by the AT2R antagonist PD 123,319 . However, the bioavailability of 60 was lower than of 8 in rat (unpublished data).…”

Section: Introductionmentioning

confidence: 91%

“…The binding affinity to the AT2R is almost tenfold lower with an unsubstituted thiazole, oxazole, or a pyrazole as compared to an imidazole or triazole attached to the scaffold. Furthermore the tetrazole derivative 57 , its isomer 58 and, the thiophene compound 59 are all inferior as ligands to the AT2R …”

Section: Introductionmentioning

confidence: 99%

“…The 2‐oxo‐pyrrolidin derivative 60, an example of a ligand containing a cyclic non‐aromatic ring, exhibited a K i value of 3.5 nM (Fig. ).…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

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“…In this aspect, compounds such as C21/M024 as well as other recently synthesized highly selective nonpeptide AT 2 receptor ligands (all leading to neurite outgrowth in NG108-15 cells) and their effectiveness to induce AT 2 receptor-dependent effects need to be further explored [212–216]. …”

Section: Discussionmentioning

confidence: 99%

The Angiotensin II Type 2 Receptor in Brain Functions: An Update

Guimond

Gallo‐Payet

2012

International Journal of Hypertension

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Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2 receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2 receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2 receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2 receptor in the brain must also consider the Ang IV/AT4 receptor.

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“…The best analogue prepared was compound E (Fig. 12) which induced neurite elongation in NG 108-15 cells and served as a potent and selective AT 2 R agonist 45 . These scientists also synthesized another analog of MO24/C21 -compound F, a selective AT 2 R antagonist, which is meta-rather than parasubstituted on the phenyl ring 46 .…”

Section: Fig 11: the Compounds With Dual At 1 R Antagonism And Pparγmentioning

confidence: 99%

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2017

IJPSR

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ABSTRACT:The renin-angiotensin system (RAS) plays an important role in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. In addition to a discussion of the current understanding of the chemical structures and the modes of action of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor (ATR) antagonists, review includes their SAR analysis and chemical modification for improving their activity. Nowadays different modeling strategies are underway to develop tailor made molecules with the best of properties among nonpeptide renin inhibitors, dual action receptor antagonists (e.g. angiotensin and endothelin antagonists, ACE/NEP inhibitors, AT 1 /TxA 2 antagonists, balanced AT 1 /AT 2 antagonists), triple inhibitors. In the first part is given an overview of various ACE inhibitors. The second part is devoted to overview of angiotensin receptor antagonists. The advances that have been made, new opportunities, and future directions of design and development of these classes have been discussed.

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Selective angiotensin II AT2 receptor agonists with reduced CYP 450 inhibition

Cited by 26 publications

References 31 publications

Small‐molecule AT2 receptor agonists

Small‐molecule AT2 receptor agonists

The Angiotensin II Type 2 Receptor in Brain Functions: An Update

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