Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists

doi:10.1016/j.bmcl.2011.03.084

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 10, 15 May 2011, Pages 2832-2835

https://doi.org/10.1016/j.bmcl.2011.03.084 Get rights and content

Abstract

A weak antagonist of the pyrimidinergic receptor P2Y₁₄ containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y₁₄ antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies.

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Molecular pharmacology of P2Y receptor subtypes
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Professor Geoffrey Burnstock proposed the concept of purinergic signaling via P1 and P2 receptors. P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular adenine and uracil nucleotides. Eight mammalian P2Y receptor subtypes have been identified. They are divided into two subgroups (P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y₁₁) and (P2Y₁₂, P2Y₁₃, and P2Y₁₄). P2Y receptors are found in almost all cells and mediate responses in physiology and pathophysiology including pain and inflammation. The antagonism of platelet P2Y₁₂ receptors by cangrelor, ticagrelor or active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel reduces the ADP-induced platelet aggregation in patients with thrombotic complications of vascular diseases. The nucleotide agonist diquafosol acting at P2Y₂ receptors is used for the treatment of the dry eye syndrome. Structural information obtained by crystallography of the human P2Y₁ and P2Y₁₂ receptor proteins, site-directed mutagenesis and molecular modeling will facilitate the rational design of novel selective drugs.
Design, synthesis and evaluation of 3-amide-5-aryl benzoic acid derivatives as novel P2Y<inf>14</inf>R antagonists with potential high efficiency against acute gouty arthritis
2021, European Journal of Medicinal Chemistry
P2Y₁₄ nucleotide receptor plays important roles in series of physiological and pathologic events especially associated with immune and inflammation. Based on the 3-amide benzoic acid scaffold reported by our group previously, a series of 5-aryl-3-amide benzoic acid derivatives were designed as novel P2Y₁₄ antagonists with improved pharmacokinetic properties. Among which compound 11m showed most potent P2Y₁₄ antagonizing activity with an IC₅₀ value of 2.18 nM, furnishing greatly improved water solubility and bioavailability compared with PPTN. In MSU-induced acute gouty arthritis model in mice, 11m exerted promising in vivo efficacy in alleviating mice paw swelling and inflammatory infiltration. Mechanistically, compound 11m notably blocked pyroptosis of macrophages through inhibiting NLRP3 inflammasome activation. This work may contribute to the identification of potential therapeutic agents to intervene in acute gouty arthritis.
Design, synthesis and anti-inflammatory evaluation of 3-amide benzoic acid derivatives as novel P2Y<inf>14</inf> receptor antagonists
2019, European Journal of Medicinal Chemistry
Citation Excerpt :
Recent studies have shown that the antagonism of P2Y14R has a potential therapeutic effect on diabetes with mixed effects in insulin function [11,12]. Several types of P2Y14R antagonists, such as pyrido [4,3-d]pyrimidines (Fig. 1, 1) [14], 2-naphthalic acids (Figs. 1, 2 and 3) [8,15,16], and 3-alkynyl or triazole benzoic acids (Figs. 1, 4 and 5) [17–20] have been reported up to date [13]. One of the reported 2-naphthoic acid derivatives, 4-(4-(piperidin-4-yl)-phenyl)-7- (4-(trifluoromethyl)-phenyl)-2-naphthoic acid (PPTN, 2), was considered to be the most potent and selective P2Y14R inhibitor (P2Y14R IC50 = 0.4 nM, other P2YRs subtype > 10 μM) [8].
The P2Y₁₄ receptor (P2Y₁₄R) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2Y₁₄R antagonists. The most potent antagonist, 16c, showed comparable activity (IC₅₀ = 1.77 nM) to PPTN, the most potent P2Y₁₄R antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.
Pharmacology of P2Y receptors
2019, Brain Research Bulletin
Citation Excerpt :
A 4,7-disubstituted 2-naphthoic acid analogue (PPTN) is a selective and potent (affinity below 1 nM) P2Y14 receptor antagonist (Table 2; Barrett et al., 2013). In addition to PPTN, further non-nucleotide P2Y14 receptor antagonists have been developed (Gauthier et al., 2011; Guay et al., 2011; Robichaud et al., 2011). Potent novel antagonists derived from 3-(4-phenyl-1 H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid as scaffold include a 3-aminopropyl congener (MRS4458) and phenyl p-carboxamide derivative (MRS4478; Yu et al., 2018)
P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes divided into two subgroups (P2Y₁, P2Y₂, P2Y₄, P2Y₆, and P2Y₁₁) and (P2Y₁₂, P2Y₁₃, and P2Y₁₄). The P2Y receptors are expressed in various cell types and play important roles in physiology and pathophysiology including inflammatory responses and neuropathic pain. The antagonism of P2Y₁₂ receptors is used in pharmacotherapy for the prevention and therapy of cardiovascular events. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel inhibit platelet P2Y₁₂ receptors and reduce thereby platelet aggregation. The P2Y₂ receptor agonist diquafosol is used for the treatment of the dry eye syndrome. The P2Y receptor subtypes differ in their amino acid sequences, their pharmacological profiles and their signaling transduction pathways. Recently, selective receptor ligands have been developed for all subtypes. The published crystal structures of the human P2Y₁ and P2Y₁₂ receptors as well as receptor models will facilitate the development of novel drugs for pharmacotherapy.
Recent progress on the discovery of P2Y<inf>14</inf> receptor antagonists
2019, European Journal of Medicinal Chemistry
Citation Excerpt :
Collectively, the physiological implications of P2Y14R remains to be further elucidated, however, P2Y14R has been proved to be a potential therapeutic target for inflammation, diabetes, bone disorders and immune responses based on the experimental observations. Using a FLIPR (fluorometric imaging plate render) calcium mobilization assay in HEK cells, a high-throughput screening (HTS) was carried out on the Merck compound library and compound 1 (Fig. 1) was identified as a weak P2Y14R antagonist [23]. Although not very potent (IC50 = 4.9 μm), compound 1 was chosen as the lead for further optimization in light of its modular structure.
The P2Y₁₄ receptor (P2Y₁₄R), a G protein-coupled receptor (GPCR), is activated by extracellular nucleotides. P2Y₁₄R is involved in inflammatory, diabetes, immune processes and other related complications, and is therefore an attractive therapeutic target. As the three-dimensional structure of the P2Y₁₄R has not yet been elucidated, homology modeling based on the crystallography of the closely related P2Y₁₂R have been used in the structure-based design of P2Y₁₄R ligands. Several P2Y₁₄R antagonists with excellent potency and high subtype-selectivity have been discovered in recent years. In this review, development of novel small molecules as antagonists of P2Y₁₄R was described.
Tools and drugs for uracil nucleotide-activated P2Y receptors
2018, Pharmacology and Therapeutics
P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂, P2Y₁₃, and P2Y₁₄, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y₂ (UTP, also ATP and dinucleotides), P2Y₄ (UTP), P2Y₆ (UDP), and P2Y₁₄ (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y₂R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y₂R antagonist is AR-C118925 (10-01). For studies of the P2Y₄R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y₆R agonists have been developed including 5-methoxyuridine 5′-O-((R_p)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y₆R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y₁₄R agonist is available, while PPTN (10-14) represents a potent and selective P2Y₁₄R antagonist. The radioligand [³H]UDP can be used to label P2Y₁₄Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.

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Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y14 receptor antagonists

Abstract

Graphical abstract

Biochem. Pharmacol.

Eur. J. Pharmacol.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

Methods Mol. Biol.

Methods Mol. Biol.

Pharmacol. Rev.

Cell. Mol. Life Sci.

Synthesis and SAR of pyrimidine-based, non-nucleotide P2Y₁₄ receptor antagonists