Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists

doi:10.1016/j.bmcl.2008.06.055

Bioorganic & Medicinal Chemistry Letters

Volume 18, Issue 14, 15 July 2008, Pages 3848-3851

https://doi.org/10.1016/j.bmcl.2008.06.055 Get rights and content

Abstract

A novel series of cyanoguanidine-piperazine P2X₇ antagonists were identified and structure–activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X₇ receptors in addition to their ability to inhibit IL-1β release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 μM) in this latter assay and demonstrates moderate clearance in-vivo.

Graphical abstract

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Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists
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Furthermore, ester derivatives of squaric acid are easily accessible and allow the simple and selective formation of squaric acid amides and diamides with drug-like properties. In 2008, Betschmann et al. published a series of active N-cyanoguanidine-piperazine P2X7R antagonists, the most active containing 2-methylphenyl and 3,4-dimethoxybenzoyl moieties (1) [32]. We were interested in replacing the cyanoguanidine linker in 1 squaric acid diamide moiety, creating more potent P2X7R antagonists, and optimizing the physicochemical properties as well as metabolic stability of the novel compounds to generate drug-like lead structures suitable for further preclinical evaluation.
The P2X7 receptor (P2X7R) stands out among the purinergic receptors due to its strong involvement in the regulation of tumor growth and metastasis formation as well as in innate immune responses and afferent signal transmission. Numerous studies have pointed out the beneficial effects of P2X7R antagonism for the treatment of a variety of cancer types, inflammatory diseases, and chronic pain. Herein we describe the development of novel P2X7R antagonists, incorporating piperazine squaric diamides as a central element. Besides improving the antagonists’ potency from pIC₅₀ values of 5.7–7.6, ADME properties (logD_7.4 value, plasma protein binding, in vitro metabolic stability) of the generated compounds were investigated and optimized to provide novel P2X7R antagonists with drug-like properties. Furthermore, docking studies revealed the antagonists binding to the allosteric binding pocket in two distinct binding poses, depending on the substitution of the central piperazine moiety.
P2X7 Receptor as a Therapeutic Target
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Modifications of this molecule were made at the t-butyl-substituted carbon spacer that was replaced with cyclic moieties (ie piperazine). Few obtained derivatives showed comparable potency to A-740003 (Morytko et al., 2008) and some potential for the treatment of rheumatoid arthritis (RA) and other inflammatory conditions, even due to their metabolic stability and favorable pharmacokinetic properties (Betschmann et al., 2008). Further optimization of this series of compounds led to the development of the compound A-804598 (Fig. 3), showing, with the Ca2 + influx assay, an IC50 of 0.0109, 0.0099, and 0.0089 μM at the human, rat, and mouse P2X7 receptors, respectively, and a good selectivity vs the other P2X and P2Y receptors (Donnelly-Roberts, Namovic, Surber, et al., 2009).
P2X7 receptor is an ATP-gated cation channel that upon agonist interaction leads to cellular influx of Na⁺ and Ca^2 + and efflux of K⁺. P2X7 is expressed by a wide variety of cells and its activation mediates a large number of biological processes like inflammation, neuromodulation, cell death or cell proliferation and it has been associated to related pathological conditions including infectious, inflammatory, autoimmune, neurological, and musculoskeletal disorders and, in the last years, to cancer. This chapter describes structural features of P2X7, chemical properties of its agonist, antagonist, and allosteric modulators and summarizes recent advances on P2X7 receptor as therapeutic target in the aforementioned diseases. We also give an overview on recent literature suggesting that P2X7 single-nucleotide polymorphisms could be exploited as diagnostic biomarkers for the development of tailored therapies.
Structure-activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X<inf>7</inf> receptor antagonists
2015, European Journal of Medicinal Chemistry
Citation Excerpt :
A tyrosine-based antagonist, KN62 (1) [15], and its derivatives [16–21] have been developed for several years as potent and selective antagonists for the human P2X7 receptor (hP2X7R). Other derivatives, adamantine amide 2 (AZD-9056, Astrazeneca) [22], 6-azauracil 3 (CE-224,535, Pfizer) [23,24], and cyanoguanidine (4, Abbott) [25], were recently identified in pharmaceutical company drug discovery programs. Particularly, 2 and 3 were investigated in phase II clinical studies for the treatment of rheumatoid arthritis [26].
As an optimization strategy, the flexible structure of KN-62, a known P2X₇ receptor antagonist, was converted into conformationally constrained derivatives using pyrimidine-2,4-dione as the core skeleton. Various modifications at the 4-position of the piperazine moiety of the new lead compound were performed to improve P2X₇ receptor antagonistic activities, which were evaluated in HEK293 cells stably expressing the human P2X₇ receptor (EtBr uptake assay) and in THP-1 cells (IL-1β ELISA assay). According to the results, polycycloalkyl acyl or di-halogenated benzoyl substituents were much more favorable than the original phenyl group of KN-62. Among these compounds, the trifluoromethyl-chloro benzoyl derivative 18m and adamantyl carbonyl derivatives 19g–19i and 19k showed potent antagonistic effects, with IC₅₀ values ranging from 10 to 30 nM. In addition, the in vitro adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of 18m was determined to be in acceptable ranges in terms of metabolic stability and cytotoxicity. These results suggest that pyrimidine-2,4-dione derivatives may be promising novel P2X₇ receptor antagonists for the development of anti-inflammatory drugs.
Purinergic P2X receptors: Structural models and analysis of ligand-target interaction
2015, European Journal of Medicinal Chemistry
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Considering the inhibitors, different structural classes of compounds have been reported presenting orthosteric or allosteric antagonist profile at the P2X [18], like for example nucleotide derivatives (i.e. 2′,3′-O-(2,4,6-trinitrophenyl)-ATP or TNP-ATP [21]; 2′,3′-dialdehyde-ATP or oxidized-ATP/oATP, presenting irreversible antagonist activity at the P2X7 receptor), suramin-like analogues, pyrimidine or purine derivatives [22,23], anthraquinones [24]. In the last years, the great interest in particular for the P2X7 subtype as possible therapeutic target has led to the development and publication of a number of antagonists for this receptor [25–38]. Several classes of P2X antagonists were discovered by screening efforts and not through structure-based studies, due to the lack of reliable structural data of P2X receptors.
The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists.
A facile and rapid synthesis of N-benzyl-2-substituted piperazines
2011, Tetrahedron Letters
Purinergic P2X<inf>7</inf> receptor antagonists: Chemistry and fundamentals of biological screening
2009, Bioorganic and Medicinal Chemistry

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^†: These authors contributed equally to this work.

^‡: Present address: SGX Pharmaceuticals, 10505 Roselle Street, San Diego, CA 92121, USA.

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Synthesis and activity of N-cyanoguanidine-piperazine P2X7 antagonists

Abstract

Graphical abstract

J. Biol. Chem.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Pain

Biorg Med. Chem. Lett.

Handb. Exp. Pharmacol.

Curr. Top. Med. Chem.

Expert Opin. Ther. Patents

Curr. Med. Chem.

Synthesis and activity of N-cyanoguanidine-piperazine P2X₇ antagonists