1. Academic Validation
  2. Design, Synthesis, and Pharmacological Evaluation of Benzimidazolo-thiazoles as Potent CXCR3 Antagonists with Therapeutic Potential in Autoimmune Diseases: Discovery of ACT-672125

Design, Synthesis, and Pharmacological Evaluation of Benzimidazolo-thiazoles as Potent CXCR3 Antagonists with Therapeutic Potential in Autoimmune Diseases: Discovery of ACT-672125

  • J Med Chem. 2022 Sep 8;65(17):11533-11549. doi: 10.1021/acs.jmedchem.2c00676.
Eva Caroff 1 Emmanuel A Meyer 1 Päivi Äänismaa 2 Sylvie Froidevaux 3 Marcel Keller 4 Luca Piali 5
Affiliations

Affiliations

  • 1 Drug Discovery Chemistry Immunology, Idorsia Pharmaceuticals Ltd., Allschwil 4123, Switzerland.
  • 2 DMPK, Idorsia Pharmaceuticals Ltd., Allschwil 4123, Switzerland.
  • 3 Private Location, Bendorf 68480, France.
  • 4 Drug Discovery Biology Immunology, Idorsia Pharmaceuticals Ltd., Allschwil 4123, Switzerland.
  • 5 Immunology, Infectious Diseases and Ophthalmology, pRED Roche, Basel 4070, Switzerland.
Abstract

The Chemokine Receptor CXCR3 allows the selective recruitment of innate and adaptive inflammatory immune cells into inflamed tissue. CXCR3 ligands are secreted after exposure to pro-inflammatory cytokines. Upon binding to CXCR3 ligands, CXCR3 expressing T-lymphocytes migrate toward sites of inflammation and can promote tissue damage. Therefore, antagonizing this receptor may provide clinical benefits for patients suffering from autoimmune diseases characterized by high concentrations of CXCR3 ligands. Herein, we report the second part of our CXCR3 discovery program where we explored the benzimidazolo-thiazole core scaffold. The optimization of potency and the mitigation of an hERG liability are described. Further pharmacokinetic considerations led to the identification of the potent CXCR3 Antagonist ACT-672125 (29). The compound showed good physicochemical properties and safety profile. In a proof-of-mechanism model of lung inflammation, ACT-672125 inhibited the recruitment of CXCR3 expressing T cells into the inflamed lung in a dose-dependent manner.

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