Discovery of benzamides as potent human β3 adrenergic receptor agonists

Zhu, Cheng; Kar, Nam Fung; Li, Bing; Costa, Melissa; Dingley, Karen H.; Salvo, Jerry Di; Ha, Sookhee; Hurley, Amanda L.; Li, Xiaofang; Miller, Randy R.; Salituro, Gino; Struthers, Mary; Weber, Ann E.; Hale, Jeffrey J.; Edmondson, Scott D.

doi:10.1016/j.bmcl.2015.11.030

Cited by 10 publications

(2 citation statements)

References 28 publications

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“…Furthermore, in models of genetically induced obesity in mice and rats, a decrease in RNAm levels within β 3 adrenergic receptors was observed [7,8]. New potential β 3 adrenergic receptors agonists are being developed and investigated all over the world [2,23]. Although at present several in vitro methods are available for preclinical trials [17] animal testing remains an essential step for introducing new drugs in therapy.…”

Section: Introductionmentioning

confidence: 99%

Experimental Pharmacological Research Regarding the Effect of Some Newly Synthesized Β-Phenylethyl Amines on the Modified Parameters of the Lipid Metabolism

Ștefănescu¹

2019

FARMACIA

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The effect of some new β-phenylethylamine derivatives on some parameters of the lipid metabolism and lipid peroxidation was investigated. The research method used was based on inducing hyperlipidaemia in rats by administering orally 4% triton in a dose of 400 mg/kg bw. The new compounds were tested against fenofibrate, the reference substance. The results have shown that compounds coded C2 and A1 induced a decrease in the total cholesterol levels, that was higher than that generated by the reference substance, compared to the control group with hyperlipidaemia. Furthermore, compounds coded C2, A6 and C3 have lowered LDL-cholesterol levels more efficiently than fenofibrate, in the hyperlipidaemia control group. All compounds except for C1 increased HDL-cholesterol levels more than the reference substance in the hyperlipidaemia control group. All compounds lowered the malonyl dialdehyde liver concentration, as a biomarker of lipid peroxidation, compared to the hyperlipemic control group. According to our results, the newly synthesized β-phenylethylamine derivatives have a statistically significant positive impact on the parameters of the lipid metabolism, possibly due to a β 3-adrenergic receptors agonist mechanism. Rezumat A fost evaluat efectul unor compuși nou sintetizați cu nucleu beta-feniletilaminic asupra parametrilor metabolismului lipidic și asupra peroxidării lipidice. Metoda de cercetare folosită s-a bazat pe inducerea hiperlipemiei la șobolan prin administrarea orală a 400 mg/kg corp triton 4%. Compuși au fost administrați pe cale orală, comparativ cu fenofibratul, utilizat ca substanță de referință. Rezultatele au arătat că doi dintre compuși, notați C2 și A1 au determinat scăderi ale colesterolului total mai mari decât cele induse de fenofibrat la șobolanii hiperlipemici. Compușii C2, A6 și C3 au determinat scăderi ale LDL colesterolului mai mari decât cele induse de fenofibrat față de martorul hiperlipemic. Toate substanțele au determinat creșteri ale HDL colesterolului, respectiv scăderi ale trigliceridelor serice (cu excepția C1), mai mari decât cele induse de fenofibrat la șobolanii hiperlipemici. Toate substanțele au scăzut concentrația malonildialdehidei hepatice, ca marker al peroxidării lipidice, comparativ cu lotul martor hiperlipemic. Conform rezultatelor obținute, substanțele nou-sintetizate prezintă efecte benefice semnificative statistic asupra parametrilor metabolismului lipidic, posibil printr-un mecanism de tip agonist asupra receptorilor beta-3 adrenergici.

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Section: Introductionmentioning

confidence: 99%

Experimental Pharmacological Research Regarding the Effect of Some Newly Synthesized Β-Phenylethyl Amines on the Modified Parameters of the Lipid Metabolism

Ștefănescu¹

2019

FARMACIA

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“…β 3 -AR agonists include phenylethanolamine molecules such as BRL 37344, GW-427353 (Solabegron), SR-58611A (Amibegron) [ 23 ], and YM-178 (Mirabegron) [ 24 ] ( Figure 1 ), while antagonists include aryloxypropanolamines such as SR 59230A, L-748337 and CGP-20712A. Despite recent efforts for obtaining new derivatives with β 3 -AR affinity [ 25 , 26 ], Mirabegron has been the only drug approved by the FDA for the treatment of overactive bladder (OAB). However, in August 2015, the FDA raised concerns due to reported cases of life-threatening upper airway angioedema, which resulted from even first administration of Mirabegron.…”

Section: Introductionmentioning

confidence: 99%

2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β3-Adrenergic Activity

et al. 2017

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The β3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β3 adrenergic activity is given.

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In silico identification of a biarylamine acting as agonist at human β3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism

Soriano-Ursúa,

Arias-Montaño,

Ocampo-Néstor

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Discovery of benzamides as potent human β3 adrenergic receptor agonists

Cited by 10 publications

References 28 publications

Experimental Pharmacological Research Regarding the Effect of Some Newly Synthesized Β-Phenylethyl Amines on the Modified Parameters of the Lipid Metabolism

Experimental Pharmacological Research Regarding the Effect of Some Newly Synthesized Β-Phenylethyl Amines on the Modified Parameters of the Lipid Metabolism

2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β3-Adrenergic Activity

In silico identification of a biarylamine acting as agonist at human β3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism

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