Short pseudopeptides containing turn scaffolds with high AT2 receptor affinity

Georgsson, Jennie; Rosenström, Ulrika; Wallinder, Charlotta; Beaudry, Hélène; Plouffe, Bianca; Lindeberg, Gunnar; Botros, Milad; Nyberg, Fred; Karlén, Anders; Gallo‐Payet, Nicole; Hallberg, Anders

doi:10.1016/j.bmc.2006.05.019

Cited by 17 publications

(28 citation statements)

References 35 publications

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“…As an example of what can be found by studies around relatively simple peptidomimics of the angiotensin II structure, the paper of Wan et al 79 demonstrating the modification of the known but non-selective AT 1 /AT 2 agonist, L-162313 ( 2 , itself related to the sartans), into the highly selective AT 2 agonist 3 (a peptidomimetic structure), led to the identification of short pseudopeptides exemplified by 4 , which is equipotent (binding affinity = 500 pM) with angiotensin II and has a better than 20,000-fold selectivity versus AT 1 , whereas angiotensin II has only a five-fold binding selectivity in the same assay, 80 as reported in our 2007 review. The chemistry leading to these compounds was reported in 2007 in greater detail by Georgsson et al 81 with a thorough discussion of the role of AT 2 receptors in a multiplicity of disease states being published in 2008.…”

Section: Resultsmentioning

confidence: 99%

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

2012

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This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003 and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1st 1981 to December 31st 2010 for all diseases world-wide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs world-wide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions, and have added a new designation “natural product botanical” or “NB” to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131 or 74.8% are other than “S” (synthetic), with 85 or 48.6% actually being either natural products or directly derived there from. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures, and have been used very successfully in the optimization of many recently approved agents, we are only able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly.

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Section: Resultsmentioning

confidence: 99%

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

2012

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“…In contrast, AT2 receptor stimulation is believed to mediate nitric oxide release and tissue repair, as well as anti-proliferative and anti-fibrotic effects [9,12,36]. Interestingly, Ang II and various peptide analogues appear to have higher binding affinity for AT2 versus AT1 receptors [37][38][39]. Though preferential affinity of Ang II for AT2 receptors in colon tissue has yet to be demonstrated, one potential outcome of ACE2 inhibition is an altered balance in receptor-mediated signal transduction in favor of this receptor.…”

Section: Discussionmentioning

confidence: 99%

Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice

Byrnes¹,

Gross²,

Ellard³

et al. 2009

Inflamm. Res.

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“…There are also reports of peptides that are proposed to act as AT2R‐selective agonists. Of these, CGP‐42112A and ( p ‐amino‐Phe6) Ang II have been most extensively utilized as research tools . Recently, the highly selective AT2R agonist β‐Pro 7 Ang III was reported.…”

Section: Introductionmentioning

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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Short pseudopeptides containing turn scaffolds with high AT2 receptor affinity

Cited by 17 publications

References 35 publications

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice

Small‐molecule AT2 receptor agonists

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