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Dorzolamide intermediates with potential anti-inflammatory activity.

Rajat Atre1, Alexander G Obukhov2, Chinmay Y Majmudar3

  • 1Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India.

European Journal of Pharmacology
|December 4, 2024
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New dorzolamide (DZD) intermediates show potent anti-inflammatory effects by targeting TIRAP signaling. These compounds are more effective than DZD in reducing inflammation and exhibit fewer side effects, offering promise for novel therapeutics.

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Area of Science:

  • Pharmacology
  • Immunology
  • Medicinal Chemistry

Background:

  • Dorzolamide (DZD) is a carbonic anhydrase (CA) inhibitor used to reduce intraocular pressure.
  • DZD possesses anti-inflammatory properties by inhibiting TIR domain-containing adaptor protein (TIRAP)-mediated signaling in macrophages.

Purpose of the Study:

  • To investigate the anti-inflammatory potential of DZD intermediates.
  • To assess if DZD intermediates can inhibit TIRAP-mediated signaling with reduced carbonic anhydrase inhibition.

Main Methods:

  • Assessed binding affinity of DZD intermediates to TIRAP and its associated kinases (PKCδ, BTK).
  • Measured the impact of DZD intermediates on inflammatory signaling pathways (TIRAP, p38 MAPK, p65).
  • Evaluated mRNA expression of pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells.
  • Determined binding energy to CA II and CA IV.
  • Tested the most effective intermediate (DRZ V) in a mouse sepsis model.

Main Results:

  • DZD intermediates demonstrated increased binding to TIRAP at the kinase interface.
  • These intermediates effectively decreased the activity of TIRAP, p38 MAPK, and p65.
  • DZD intermediates showed superior efficacy in reducing pro-inflammatory cytokine mRNA levels compared to DZD.
  • Intermediates exhibited reduced binding to CA II and CA IV, suggesting improved specificity.
  • DRZ V treatment led to improved survival in septic mice compared to DZD treatment.

Conclusions:

  • DZD intermediates are more potent in inhibiting TIRAP-mediated inflammatory signaling than DZD.
  • These intermediates offer a promising avenue for developing novel anti-inflammatory therapeutics with potentially fewer side effects.