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).
References
Jun 1, 1979·Drugs·R C HeelG S Avery
Aug 7, 1992·Journal of Medicinal Chemistry·J D BloomT H Claus
Jun 1, 1990·Trends in Pharmacological Sciences·L Manara, A Bianchetti
Aug 1, 1990·British Journal of Pharmacology·A Bianchetti, L Manara
Sep 8, 1989·Science·L J EmorineA D Strosberg
Apr 1, 1995·Brain Research. Molecular Brain Research·M RodriguezD Shire
Nov 25, 1994·Journal of Medicinal Chemistry·G KlebeT Mietzner
Jan 1, 1993·The Journal of Clinical Investigation·S KriefL J Emorine
Jul 15, 1996·The Journal of Clinical Investigation·C GauthierH Le Marec
Jan 1, 1997·Endocrinology·S CollinsR S Surwit
Feb 23, 2002·Journal of Molecular Graphics & Modelling·Alexander Golbraikh, Alexander Tropsha
Apr 17, 2002·Clinical Pharmacology and Therapeutics·Marleen A van BaakWim H M Saris
Feb 13, 2007·The Journal of Pharmacology and Experimental Therapeutics·Toshiyuki TakasuOsamu Yamaguchi
Apr 27, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jeanne StemmelinGuy Griebel
Sep 21, 2007·Journal of Chemical Information and Modeling·Christoph RückerMarkus Meringer
Mar 25, 2008·Pharmacology, Biochemistry, and Behavior·David H OverstreetGuy Griebel
Oct 15, 2008·Oncology·Maria Grazia PerroneAntonio Scilimati
Apr 14, 2009·Bioorganic & Medicinal Chemistry·Tatsuya MaruyamaMitsuaki Ohta
Jul 8, 2009·Bioorganic & Medicinal Chemistry·Tatsuya MaruyamaMitsuaki Ohta
Jun 3, 2011·Current Heart Failure Reports·Chantal GauthierJean-Luc Balligand
Aug 1, 1988·Journal of the American Chemical Society·R D CramerJ D Bunce
Mar 3, 2012·Drugs of Today·J Gras
Mar 29, 2012·SAR and QSAR in Environmental Research·A K Saxena, K K Roy
Jun 13, 2012·Chemical & Pharmaceutical Bulletin·Tatsuya MaruyamaMitsuaki Ohta
Jan 10, 2013·Journal of Computational Chemistry·Kunal RoyRudra Narayan Das
Jan 21, 2014·Journal of Medicinal Chemistry·Christopher R MoyesScott D Edmondson
Feb 18, 2015·The Journal of Organic Chemistry·Robin HertzbergChristina Moberg
Dec 29, 2015·Journal of Medicinal Chemistry·Scott D EdmondsonAnn E Weber
Jul 12, 2010·Molecular Informatics·Alexander Tropsha
Mar 10, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gastón ApablazaJaime Mella
Jun 16, 2017·Journal of Clinical Pharmacology·Marcel van GelderenCees Korstanje
Citations
May 24, 2019·International Journal of Molecular Sciences·Marcos LorcaJaime Mella
Aug 18, 2020·Journal of Biomolecular Structure & Dynamics·Adib GhalebSalah-Eddine Stiriba
Nov 15, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gaomin Zhang, Yujie Ren
Jul 6, 2021·Saudi Journal of Biological Sciences·Chandrabose SelvarajSanjeev Kumar Singh
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