Progress in the Development of Platelet‐Activating Factor Receptor (PAFr) Antagonists and Applications in the Treatment of Inflammatory Diseases

Abstract

Platelet-activating factor (PAF) and its receptor (PAFr) have been implicated in a wide range of diseases and disorders that originate from the activation of inflammatory pathways. Although the exact structure of the binding site on the PAFr remains unknown, the PAFr is a well-established therapeutic target, and an array of structurally diverse PAFr antagonists have been identified. These include compounds that are structurally similar to the natural PAF ligand, synthetic heterocycles, complex polycyclic natural products, and various metal complexes. This review provides an update on more than 20 years of progress in this area. The development and synthesis of new PAFr antagonists, structure-activity relationship studies, the biological activity of these molecules, and their therapeutic potential are discussed.

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives

“…There are several studies indicating that PAF and its receptor are critical components of the molecular processes in the development and progression of breast cancer [111,112], colorectal cancer [113], oesophageal cancer [58], lung cancer [59], liver cancer [60], pancreatic cancers [114], skin cancers [115], and various other cancers [8,107]. This has led to significant interest among researchers to develop novel therapeutics relating to PAF and its metabolism [8,116]. As aforementioned, PAF seems to be critical in cell signalling in the CNS.…”

“…Finally, apart from the various compounds presented in Table 2, research has investigated the use of various inorganic metal complexes including other structurally related and structurally dissimilar PAF-R antagonists [141]. The authors recommend the following comprehensive reviews for further information on various synthetic and inorganic metal complexes with PAF-R antagonistic properties, their structures, synthesis, and biological effects [116,141,167,185].…”

Antithrombotic and antiplatelet activity of an organometallic rhodium(I) complex incorporating a substituted thieno‐[2,3‐d]‐pyrimidine ligand: Synthesis, structural characterization, and molecular docking calculations

“…[18] Recent results in this topic have been summarized by us [13,19] and by other research groups. [20][21][22][23] Intrigued by these results, we were interested in developing neutral organometallic rhodium(I)-based compounds, as potent anti-PAF and antithrombotic agents, a class of compounds that has not been examined previously. Moreover, we wanted to further explore the influence of appropriate monodentate organic ligands that exhibit significant and diverse biological activity, on the inhibitory effect against the PAF-and thrombin-induced aggregation.…”

Platelet activating factor receptor regulates colitis-induced pulmonary inflammation through the NLRP3 inflammasome

“…22 Thus, in conditions of increased pulmonary stress of infection, PAFR may represent a crucial mediator of inflammation and inhibition or antagonism of PAFR has been considered as a therapeutic strategy for the management of pulmonary disease. 23,24 In the pulmonary inflammation associated with colitis, bacteraemia is an initiating factor and pulmonary inflammation is dependent on neutrophil recruitment from the bone marrow. 7 While these animals exhibit increased bacterial load in the lungs, the mechanism initiating neutrophil recruitment to the lung is unclear.…”