Design and Synthesis of Orally Active Quinolyl Pyrazinamides as Sigma 2 Receptor Ligands for the Treatment of...

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• The sigma 2 receptor (σ2R) is overexpressed in various cancers, serving as a biomarker for tumor proliferation.
• σ2R ligands are being explored for their theranostic potential in cancer and neurodegenerative diseases.

Purpose of the Study:

• To design and synthesize novel quinolyl pyrazinamides as selective and potent σ2R ligands.
• To evaluate the efficacy and pharmacokinetic properties of these compounds in pancreatic cancer models.

Main Methods:

• Synthesis of a series of quinolyl pyrazinamides.
• Binding affinity assays for σ2R.
• In vitro cytotoxicity assays in pancreatic cancer cell lines.
• In vivo efficacy studies in a syngeneic pancreatic cancer model.
• Pharmacokinetic profiling, including oral bioavailability assessment.

Main Results:

• Novel quinolyl pyrazinamides were synthesized, exhibiting sub-micromolar potency against σ2R.
• Compounds 14 (JR1-157) and 17 (JR2-298) showed high binding affinity (K_i = 47 nM and 10 nM, respectively).
• Compound 14 demonstrated 60% oral bioavailability, significant in vivo efficacy in a pancreatic cancer model, and enhanced cytotoxicity in the presence of copper.
• Compound 14 is water-soluble, metabolically stable, orally active, and upregulates the autophagy marker LC3B.

Conclusions:

• Compound 14 is a promising candidate for pancreatic cancer treatment.
• The observed copper-dependent cytotoxicity suggests a novel therapeutic mechanism.
• Further development of compound 14 is warranted for pancreatic cancer theranostics.