Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Marcos LorcaJaime Mella

Abstract

The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r² ncv = 0.993 and 0.984 and values of r² test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q², r², r² m , etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).

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Citations

Nov 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gaomin Zhang, Yujie Ren
Jul 10, 2021·Investigative Ophthalmology & Visual Science·Murat Topcuoglu, Fatih Aslan
Sep 22, 2021·International Journal of Urology : Official Journal of the Japanese Urological Association·Shizuo YamadaKazumasa Shinozuka

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Software Mentioned

Windows
SE
Gaussian
Sybyl X -
ChemBio3D
Sybyl
ChemDraw
CoMFA
CoMSIA
All

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