Rational Design of Dual-Target Molecules via a Fragment-Merging Strategy: TGR5 Agonism and SSTR5 Antagonism

Area of Science:

• Pharmacology
• Medicinal Chemistry
• Endocrinology

Background:

• TGR5 agonists are promising for metabolic disorders but face challenges with gallbladder filling.
• SSTR5 antagonism boosts GLP-1 secretion and gallbladder contraction, aiding glycemic control and counteracting TGR5 side effects.

Purpose of the Study:

• To design and synthesize dual-target small molecules activating TGR5 and antagonizing SSTR5.
• To evaluate the efficacy and safety of these dual-action compounds for metabolic disorders.

Main Methods:

• Rational design and synthesis of small molecules targeting both TGR5 and SSTR5.
• In vitro assessment of compound activity (EC50, IC50) and in vivo evaluation of glucose tolerance and gallbladder effects.

Main Results:

• Compound 19 demonstrated potent dual activity (hTGR5 EC50 = 5.91 nM; hSSTR5 IC50 = 4.37 nM).
• Despite suboptimal properties, compound 19 improved glucose tolerance and reduced gallbladder filling in vivo.
• The series showed potential but required optimization of physicochemical and metabolic properties.

Conclusions:

• Dual TGR5/SSTR5 modulation represents a viable therapeutic strategy for metabolic disorders.
• This approach offers potent metabolic efficacy with a potentially reduced risk of adverse effects like gallbladder filling.