Discovery of Irbesartan Derivatives as BLT2 Agonists by Virtual Screening

Hernández‐Olmos, Víctor; Heering, Jan; Bischoff-Kont, Iris; Kaps, Alexander; Rajkumar, Rinusha; Liu, Ting; Fürst, Robert; Steinhilber, Dieter; Proschak, Ewgenij

doi:10.1021/acsmedchemlett.1c00240

Cited by 5 publications

(9 citation statements)

References 15 publications

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“…Consequently, we used cells co-expressing BLT2 in combination with GNAi2, which were stimulated with forskolin for a suitable basal activation of adenylate cyclase. The BLT2 reference agonist 1 and also irbesartan, which we recently identified as a BLT2 ligand, both activated BLT2 as seen in a reduction of cAMP, Figure A.…”

Section: Chemistrymentioning

confidence: 90%

Development and Characterization of a Fluorescent Ligand for Leukotriene B4 Receptor 2 in Cells and Tissues

et al. 2022

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The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), which has been proposed as a promising therapeutic target for diabetic wound healing and gastrointestinal lesions. In this study, the rational design of a fluorescent probe based on the synthetic BLT2 agonist CAY10583 is described. The synthesis of several derivatives of CAY10583 coupled to fluorescein resulted in a traceable ligand suitable for different fluorescence-based techniques. An HTRF-based displacement assay (Tag-lite) on stably transfected CHO-K1 cells was developed to characterize binding properties of diverse BLT2 ligands. Highly specific binding to the BLT2 receptor was demonstrated in staining experiments on mouse skin tissue, and specific modulation of BLT2-induced cAMP signaling provided further evidence for receptor binding and ligand functionality. In conclusion, the fluorescent ligands developed in this study are suitable to investigate the pharmacology of BLT2 receptor ligands in a variety of assay systems.

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Section: Chemistrymentioning

confidence: 90%

Development and Characterization of a Fluorescent Ligand for Leukotriene B4 Receptor 2 in Cells and Tissues

et al. 2022

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“…The prime focus of drug discovery research is to develop safe, economically viable bioactive lead molecules for the treatment of diseases, but it requires an assiduous process with plenty of time and overpriced procedures. [1][2][3] For the synthesis of lead bioactive compounds, researchers from all around the world are working to provide environmentally friendly synthetic processes DOI: 10.1002/masy.202300008 and secure reagents. [4,5] Instead of attempting to synthesize a new bioactive lead molecule, it is better to do drug repurposing methods such as structural modification of commercial drugs.…”

Section: Introductionmentioning

confidence: 99%

“…[ 14 ] Long‐term high blood pressure is the main risk factor for stroke or heart failure. [ 15 ] Hypertension is a condition where the blood pressure in the arteries becomes increased. Irbesartan causes significant side effects such as dizziness, diarrhea, drowsiness, muscle aches, and heartburn.…”

Section: Introductionmentioning

confidence: 99%

Novel Synthesis and Characterization of Irbesartan Derivative an Anti‐Hypertensive Active Pharmaceutical Ingredient (API)

Tomar,

Jayakumar,

Saxena

2024

Macromolecular Symposia

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The current research focuses on the design, method development, characterization, and clinical assessment of novel irbesartan medication compounds. The objective of synthetic modification of a drug molecule is to achieve the desired properties such as enhancing the pharmacological properties and minimizing the side effects. It is a biphenyl tetrazole and an aza‐spiro compound, a highly selective, potent nonpeptide compound that belongs to the sartan group, an authorized type‐1 angiotensin II receptor (AT1), dilates the blood vessels and is used in curing of to treat high blood pressure, cardiac arrest, and renal disease in diabetics. To achieve the structural modification of the irbesartan drug, the researcher prepared the FeCl3/SiO2 catalyst and successfully used it for the acetylation, chloro acetylation reaction of irbesartan with acetyl chloride and chloroacetyl chloride. Further, the reaction is performed in presence of the catalyst and without a catalyst to elucidate the role of the catalyst. With the aid of TLC, FT‐IR, and UV–visible spectral methods, the structural interpretation of synthesized derivatives is completed. The present work illustrates a novel method of synthesis of irbesartan derivatives through safe and convenient procedures. The pharmacological evaluation of synthetic derivatives and green chemistry protocol of synthesis is under progress.

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“…Indeed, imidazolones have recently been shown to be a nonaromatic bioisostere of the amide bond with favorable pharmacological properties, creating a compelling need for further exploration (Figure B) . Additionally, (4 H )-imidazolones are high-value heterocycles appreciated for their antihypertensive, anticancer, antipsychotic, antiviral, and cytotoxic effects; they are also known to the agrochemical field as potent broad spectrum herbicides (Figure , 1 – 6 ). Thus, new methods to form imidazolones under gentle conditions will enable access to amino-acid-derived imidazolone natural products that have yet to be synthesized …”

Section: Introductionmentioning

confidence: 99%

“…Selected examples of (4 H )-imidazolones present in pharmaceuticals, − herbicides, and natural products , .…”

Section: Introductionmentioning

confidence: 99%

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

Wall,

Sharma,

O’Brien

et al. 2024

J. Am. Chem. Soc.

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Imidazolones represent an important class of heterocycles present in a wide range of pharmaceuticals, metabolites, and bioactive natural products and serve as the active chromophore in green fluorescent protein. Recently, imidazolones have received attention for their ability to act as a nonaromatic amide bond bioisotere which improves pharmacological properties. Herein, we present a tandem amidine installation and cyclization with an adjacent ester to yield (4H)-imidazolone products. Using amino acid building blocks, we can access the first examples of αchiral imidazolones that have been previously inaccessible. Additionally, our method is amenable to on-resin installation which can be seamlessly integrated into existing solid-phase peptide synthesis protocols. Finally, we show that peptide imidazolones are potent cis-amide bond surrogates that preorganize linear peptides for head-to-tail macrocyclization. This work represents the first general approach to the backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.

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Discovery of Irbesartan Derivatives as BLT2 Agonists by Virtual Screening

Cited by 5 publications

References 15 publications

Development and Characterization of a Fluorescent Ligand for Leukotriene B4 Receptor 2 in Cells and Tissues

Development and Characterization of a Fluorescent Ligand for Leukotriene B4 Receptor 2 in Cells and Tissues

Novel Synthesis and Characterization of Irbesartan Derivative an Anti‐Hypertensive Active Pharmaceutical Ingredient (API)

General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

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