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Design and exploration of gut-restricted bifunctional molecule with TGR5 agonistic and DPP4 inhibitory effects for

Fanghui Han1, Mengmeng Ning2, Kai Wang2

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.

European Journal of Medicinal Chemistry
|August 27, 2022
PubMed

Insights

New gut-restricted bifunctional molecules targeting TGR5 and DPP4 show promise for ulcerative colitis (UC) treatment. These compounds leverage dual mechanisms while minimizing systemic side effects, offering a safer therapeutic approach for UC.

Area of Science:

  • Gastroenterology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Ulcerative colitis (UC) presents complex challenges in treatment due to its multifactorial nature.
  • Existing therapies are limited, necessitating novel therapeutic strategies.
  • TGR5 and DPP4 pathways offer therapeutic potential for UC by modulating GLP-2 levels, but systemic administration causes adverse effects like gallbladder filling.

Purpose of the Study:

  • To design and synthesize novel gut-restricted TGR5-DPP4 bifunctional molecules for ulcerative colitis (UC) treatment.
  • To mitigate systemic side effects associated with TGR5 and DPP4 activation.
  • To explore a new therapeutic avenue for UC by combining multitargeting and gut restriction.

Main Methods:

  • Synthesis of a series of high-potency TGR5-DPP4 bifunctional molecules.
  • Incorporation of gut-restriction strategies to limit systemic exposure.
  • Evaluation of compound efficacy in a mouse colitis model.
  • Assessment of gallbladder safety profiles.

Main Results:

  • Successfully developed potent TGR5-DPP4 bifunctional molecules with gut-restricted properties.
  • Racemic compound 15 demonstrated favorable intestinal distribution and efficacy in a preclinical colitis model.
  • Compound 15 exhibited good safety regarding gallbladder-related side effects.

Conclusions:

  • Gut-restricted TGR5-DPP4 bifunctional molecules represent a feasible and potentially safer therapeutic strategy for ulcerative colitis (UC).
  • This approach effectively utilizes the benefits of TGR5 and DPP4 pathways while avoiding systemic adverse effects.
  • The findings offer a novel insight for the development of next-generation anti-UC drugs.
Keywords:
Bifunctional moleculeDPP4Gut-restrictedTGR5Ulcerative colitis

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