Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X₇ Receptor Antagonist

Abstract

Adamantanyl benzamide 1 was identified as a potent P2XR antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2XR antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2XR polymorphisms.

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

“…Studies over the past decades have collected substantial evidence to support the importance of alterations in the innate immune system function in the pathophysiology of mood disorders (Bauer et al, 2014;Bhattacharya and Drevets, 2017;Brown et al, 2017;Dantzer et al, 2008;Iwata et al, 2013;Jones and Thomsen, 2013;Kaufmann et al, 2017;Maes et al, 2012;Raison et al, 2006;Slavich and Irwin, 2014;Wohleb et al, 2016;Yirmiya et al, 1999). For example, there were significant increases in the expression of NLRP3 and caspase-1 in blood cells from MDD patients (Alcocer-Gomez et al, 2014).…”

“…In addition, treatment with trishomocubanyl and nido-1,2-carboranyl Cs significantly reduced depressivelike behaviours in mice in the FST, suggesting that these compounds are able to penetrate BBB and elicit antidepressant activity (Wilkinson et al, 2014). The same group has recently characterized a series of bioisosteres of adamantane benzamide and shown that several compounds with a BBB penetrability after administration via intravenous injection, including trifluorinated benzamide (compound 34) (Wilkinson et al, 2017). This compound blocks the human and mouse P2X7 receptors with IC50 values of 28 nM and 158 nM, respectively, in a Ca 2+ influx assay, or the human P2X7 receptor with IC50 value of 34 nM in a dye uptake assay.…”

“…They also have characterized in another recent study a series of adamantyl cyanoguanidine hybrid compounds by combining AstraZeneca's adamantyl amide scaffold and Abbott's cyanoguanidine scaffold, for example, compound 35 (Tab.1) (O' Brien-Brown et al, 2017). This compound inhibits the P2X7 receptor in a dye uptake assay with an IC50 value of 69 nM and via intraperitoneal administration depressive-like behaviours in mice examined in the FTS, demonstrating its BBB penetrability (O'Brien-Brown et al, 2017). Fantoni et al have developed a structural derivative of A-804598, i.e., 18 F-EFB as a PET tracer designed based on molecular docking (Fantoni et al, 2017).…”

The P2X7 receptor tracer [11C]SMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: a first-in man study

“…To a lesser extent, expression of P2X 7 receptor has also been found in grey matter on astrocytes, oligodendrocytes, and neurons [11]. Moreover, it was shown that the radioligand [ 11 C]SMW139 selectively binds to the P2X 7 receptor with high affinity in preclinical in vivo studies and in post-mortem human tissues [8,[12][13][14].…”

AP2RX7single nucleotide polymorphism haplotype promotes exon 7 and 8 skipping and disrupts receptor function

“…Whole-cell lysates were immunoblotted with anti-EE antibody. Proteins were detected at ~68, 31 and 58 kDa that corresponds to the expected molecular weights (MW) of P2X7A (solid arrow), P2X7E (chevron arrow), and P2X7L (thin arrow), respectively. Panels are from the same image with irrelevant lanes cropped out.…”