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Molecules 2018, 23(5), 1191; https://doi.org/10.3390/molecules23051191

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

1
Escuela de Quimica y Farmacia, Facultad de Medicina, Universidad Andres Bello, Quillota 980, Viña del Mar 2531015, Chile
2
Centro de Nanotecnología Aplicada, Facultad de Ciencias, Universidad Mayor, Camino la Pirámide 5750, Huechuraba, Santiago 8580000, Chile
3
Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Sergio Livingstone 1007, Independencia, Santiago 8380492, Chile
4
Facultad de Ciencia, Universidad San Sebastián, Lago Panguipulli 1390, Puerto Montt 5501842, Chile
5
Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Quillota 980, Viña del Mar 2531015, Chile
6
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Avda. Vicuña Mackenna 4860, Macul, Santiago 7820436, Chile
7
Centro de Investigación Farmacopea Chilena (CIFAR), Universidad de Valparaíso, Av. Gran Bretaña 1111, Valparaíso 2360102, Chile
8
Instituto de Química y Bioquímica, Facultad de Ciencias, Universidad de Valparaíso, Av. Gran Bretaña 1111, Valparaíso 2360102, Chile
*
Author to whom correspondence should be addressed.
Received: 11 April 2018 / Revised: 10 May 2018 / Accepted: 13 May 2018 / Published: 16 May 2018
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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 r2ncv = 0.993 and 0.984 and values of r2test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). View Full-Text
Keywords: β3-adrenergic receptor; obesity; diabetes; overactive bladder; aryloxypropanolamines; mirabegron; vibegron; 3D-QSAR; CoMFA; CoMSIA β3-adrenergic receptor; obesity; diabetes; overactive bladder; aryloxypropanolamines; mirabegron; vibegron; 3D-QSAR; CoMFA; CoMSIA
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lorca, M.; Morales-Verdejo, C.; Vásquez-Velásquez, D.; Andrades-Lagos, J.; Campanini-Salinas, J.; Soto-Delgado, J.; Recabarren-Gajardo, G.; Mella, J. 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 2018, 23, 1191.

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