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

Abstract

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.

Keywords: CoMSIA; QSAR; beta-3 adrenergic receptor; diabetes; indole; mirabegron; obesity; vibegron.

Figure 1

Structure of selected β₃-adrenergic agonists and compound 9, the most potent of the analyzed series.

Figure 2

Graphics of Actual versus predicted pEC₅₀ for models: 15 (left); and 30 (right).

Figure 3

CoMSIA-SA model around compound 9, the most potent of the series. (A) Steric contour map. Green contours indicate regions where bulky groups improve activity, whereas yellow contours indicate regions were bulky groups decreases activity. (B) Hydrogen-bond acceptor contour map. Magenta contours indicate regions where hydrogen-bond acceptor groups increase activity, whereas red contours indicate regions where hydrogen-bond acceptor groups decrease activity.

Figure 4

CoMSIA DA model around compound 9, the most potent of the series. (A) Donor contour map. Cyan contours indicate regions where hydrogen-bond donors increase activity, whereas purple contours indicate regions where hydrogen-bond donors decrease activity. (B) Acceptor contour map. Colors have the same meaning as explained in Figure 3B.

Figure 5

Graphic of actual against predicted pEC₅₀ for Equation (3).

Figure 6

Structure–activity relationships derived from CoMSIA/Hansch studies.