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

Marcos Lorca, Cesar Morales-Verdejo, David Vásquez-Velásquez, Juan Andrades-Lagos, Javier Campanini-Salinas, Jorge Soto-Delgado, Gonzalo Recabarren-Gajardo, Jaime Mella

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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).

Original languageEnglish
Article number1191
JournalMolecules
Volume23
Issue number5
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • 3D-QSAR
  • Aryloxypropanolamines
  • CoMFA
  • CoMSIA
  • Diabetes
  • Mirabegron
  • Obesity
  • Overactive bladder
  • Vibegron
  • Β3-adrenergic receptor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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