From lead to clinic: A review of the structural design of P2X7R antagonists

Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury

“…The 2-chloro-3trifluoromethylphenyl group was reported to be a promising substituent, widely used in the structural design of P2X7R antagonists. 5 In our study, compound 3c with this substituent exhibited a moderate antagonistic effect on hP2X7R but had poor mP2X7R potency. Subsequently, we retained the 2-Cl and introduced additional substituents at the C4−C6 positions of the benzene ring (3d−3g).…”

“…Most compounds are inactive in rodents, thereby hindering their further study in relevant animal models. 5 As a result, the identification of safe and effective P2X7R antagonists with reasonable pharmacokinetic parameters and good cross-species activity is necessary. The electrostatic potential (ESP) surface is a popular method for visualizing molecular electrostatic properties, allowing the identification of electrostatically matched or mismatched regions and facilitating the comparison of multiple ligands with different substituents or core scaffolds.…”

“…Additionally, the presence of halogen-substituted pyridine motifs (compounds 9−12 in Figure 3) is another recurring feature observed in P2X7R antagonists. 5 Hence, by combining these three pharmacophores, we obtained the initial hit compound, as depicted in Figure 2C. The triazole moiety, due to the presence of numerous lone pair electrons, is prone to be attracted by a unit positive charge, resulting in energy reduction and exhibiting a negative ESP (−35.68 and −27.73 kcal/mol).…”

“…24 AZD9056 (AstraZeneca) and CE-224535 (Pfizer) were both evaluated for the treatment of rheumatoid arthritis and osteoarthritis but were discontinued in phase II due to poor efficacy. 5 Meanwhile, EVT 401 by Evotec, another P2X7R antagonist for the treatment of rheumatoid arthritis, is currently undergoing phase II clinical trials, but its reports are not publicly available. In addition, SGM-1019, BIL-010-t, and AK-1780 are also in clinical studies, but their structures remained undisclosed.…”

“…The structure of P2X7R is unique, with a long intracellular C-terminus consisting of approximately 200 amino acid residues, accounting for 40% of the entire protein content. P2X7R plays crucial roles in channel formation, protein interactions, and activation of various signaling pathways, including PI3K/AKT and AMPK-PRAS40-mTOR pathways, as well as different downstream signals such as the NLRP3 inflammasome. − P2X7R activation under pathological conditions makes it an attractive drug target for the treatment of chronic pain, kidney disease, cancer, etc. − In addition, P2X7R is widely distributed in glial cells and immune cells of the central nervous system (CNS), mediating multiple cellular events, such as inflammatory responses, mitochondria dysfunction, and apoptosis. − Pharmacological inhibition of P2X7R has important pharmaceutical value in the treatment of CNS disease, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, insomnia, depression, and so on. − …”