Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure-Guided Amelioration of Its CYP3A4 Induction Profile

Abstract

The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types, especially those involved in inflammatory and immune processes. High-throughput screening led to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased pregnane X receptor (PXR) binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP 3A4 induction for compounds 71 and 73. Unfortunately, the in vivo pharmacokinetic (PK) profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as a potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, and the antiinflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse complete Freund's adjuvant (CFA) inflammatory pain model.

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

“…The sulfonamide BAY-1797 ( 33) was recently presented as a compound with an IC 50 of 210 nM at the hP2X4 receptor and high selectivity (Werner et al, 2019). This antagonist shows high water solubility and no brain penetration.…”

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

“…In contrast, the recently described sulfonamide derivative BAY-1797 ( 23) [40] is similarly potent at human, rat, and mouse P2X4 receptors showing good P2X4 selectivity but moderate potency. The allosteric antagonist is well watersoluble.…”

Inhibiting endocytosis in CGRP+ nociceptors attenuates inflammatory pain-like behavior

“…4g). Using a dynamic weight bearing apparatus, we were able to measure weight borne on each paw following injury which functions as a measure of non-evoked inflammatory hyperalgesia [37][38][39][40] . In this assay, weight borne on the inflamed hind paw was significantly increased 48 h following AP2 peptide injection (Fig.…”