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Phosphodiesters as GPR84 Antagonists for the Treatment of Ulcerative Colitis

Lin-Hai Chen1, Qing Zhang1,2,3, Yu-Feng Xiao1,4

  • 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Journal of Medicinal Chemistry
|February 23, 2022
PubMed

Insights

Researchers identified a new compound, compound 33, that acts as a GPR84 antagonist. This novel drug candidate shows promise in treating inflammatory diseases like ulcerative colitis by reducing inflammation and disease symptoms.

Area of Science:

  • Pharmacology
  • Immunology
  • Medicinal Chemistry

Background:

  • GPR84 is a pro-inflammatory receptor implicated in fibrotic and inflammatory conditions.
  • Existing GPR84 antagonists are limited, necessitating new therapeutic options.
  • GPR84 antagonists are under investigation for ulcerative colitis, idiopathic pulmonary fibrosis, and nonalcoholic steatohepatitis.

Purpose of the Study:

  • To discover and optimize novel GPR84 antagonists.
  • To evaluate the therapeutic potential of a new compound in an inflammatory disease model.

Main Methods:

  • High-throughput screening identified a phosphodiester hit compound.
  • Structural optimization yielded compound 33 with enhanced potency.
  • In vitro assays assessed calcium mobilization and neutrophil/macrophage chemotaxis.
  • A DSS-induced mouse model of ulcerative colitis was used for in vivo evaluation.

Main Results:

  • Compound 33 demonstrated improved potency in calcium mobilization assays.
  • Compound 33 effectively inhibited GPR84-mediated neutrophil and macrophage chemotaxis.
  • In a colitis model, compound 33 significantly reduced disease activity and symptoms.
  • Compound 33's efficacy was comparable to 5-aminosalicylic acid in the colitis model.

Conclusions:

  • Compound 33 is a potent and selective GPR84 antagonist.
  • Compound 33 exhibits therapeutic potential for ulcerative colitis.
  • Further drug development of compound 33 is warranted for inflammatory diseases.

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