Recent progress on the discovery of P2Y14 receptor antagonists

Lu, Ran; Zhang, Zhenguo; Jiang, Cheng

doi:10.1016/j.ejmech.2019.04.068

Cited by 21 publications

(19 citation statements)

References 34 publications

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“…It recognizes UDP and sugar derivatives of UDP as activators, inhibiting the production of cAMP as its principal signaling mechanism [61]. Although the crystal structure of the P2Y 14 receptor has not been elucidated, Lu et al (2019) have postulated new antagonists of this receptor by using homology modeling based on the three-dimensional structure of the P2Y 12 receptor [62]. This approach has allowed researchers to propose more refined phenyltriazole structures, test the effects of different pharmacophores and develop the structure-activity relationship (SAR) of new antagonists for the P2Y 14 receptor.…”

Section: P2y 14 Receptormentioning

confidence: 99%

Structure–activity features of purines and their receptors: implications in cell physiopathology

2022

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The purine molecular structure consists of fused pyrimidine and imidazole rings. Purines are main pieces that conform the structure of nucleic acids which rule the inheritance processes. Purines also work as metabolic intermediates in different cell functions and as messengers in the signaling pathways throughout cellular communication. Purines, mainly ATP and adenosine (ADO), perform their functional and pharmacological properties because of their structural/chemical characteristics that make them either targets of mutagenesis, mother frameworks for designing molecules with controlled effects (e.g. anti-cancer), or chemical donors (e.g., of methyl groups, which represent a potential chemoprotective action against cancer). Purines functions also come from their effect on specific receptors, channel-linked and G-protein coupled for ATP, and exclusively G-coupled receptors for ADO (also known as ADORAs), which are involved in cell signaling pathways, there, purines work as chemical messengers with autocrine, paracrine, and endocrine actions that regulate cell metabolism and immune response in tumor progression which depends on the receptor types involved in these signals. Purines also have antioxidant and anti-inflammatory properties and participate in the cell energy homeostasis. Therefore, purine physiology is important for a variety of functions relevant to cellular health; thus, when these molecules present a homeostatic imbalance, the stability and survival of the cellular systems become compromised.

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Section: P2y 14 Receptormentioning

confidence: 99%

Structure–activity features of purines and their receptors: implications in cell physiopathology

2022

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“…In specified experiments, P2Y14 was inhibited using the 4,7-disubstituted 2-naphthoic acid derivative, PPTN (termed Y14 inh in this study), which is potent and selective towards P2Y 14 [78]. 100 nM Y14 inh dosing (0.1% DMSO as a vehicle) was informed by prior work demonstrating that Y14 inh has a nanomolar IC 50 [49].…”

Section: Pharmacological Inhibition Of P2y 14mentioning

confidence: 99%

Role of UDP-Sugar Receptor P2Y14 in Murine Osteoblasts

Mikolajewicz

Komarova

2020

IJMS

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The purinergic (P2) receptor P2Y14 is the only P2 receptor that is stimulated by uridine diphosphate (UDP)-sugars and its role in bone formation is unknown. We confirmed P2Y14 expression in primary murine osteoblasts (CB-Ob) and the C2C12-BMP2 osteoblastic cell line (C2-Ob). UDP-glucose (UDPG) had undiscernible effects on cAMP levels, however, induced dose-dependent elevations in the cytosolic free calcium concentration ([Ca2+]i) in CB-Ob, but not C2-Ob cells. To antagonize the P2Y14 function, we used the P2Y14 inhibitor PPTN or generated CRISPR-Cas9-mediated P2Y14 knockout C2-Ob clones (Y14KO). P2Y14 inhibition facilitated calcium signalling and altered basal cAMP levels in both models of osteoblasts. Importantly, P2Y14 inhibition augmented Ca2+ signalling in response to ATP, ADP and mechanical stimulation. P2Y14 knockout or inhibition reduced osteoblast proliferation and decreased ERK1/2 phosphorylation and increased AMPKα phosphorylation. During in vitro osteogenic differentiation, P2Y14 inhibition modulated the timing of osteogenic gene expression, collagen deposition, and mineralization, but did not significantly affect differentiation status by day 28. Of interest, while P2ry14-/- mice from the International Mouse Phenotyping Consortium were similar to wild-type controls in bone mineral density, their tibia length was significantly increased. We conclude that P2Y14 in osteoblasts reduces cell responsiveness to mechanical stimulation and mechanotransductive signalling and modulates osteoblast differentiation.

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“…29 However, compound 2 suffers from poor solubility and low oral bioavailability due to its high lipophilicity and zwitterionic character. 30 To overcome these shortcomings, several efforts have been made, among which compounds 7 and 8 were reported by our group. The 3-amide benzoic acid moiety in compounds 7 and 8 acts as a bioisosteric replacement for the hydrophobic and unwieldy naphthalene ring of PPTN that could reduce the rigid character and preserve receptor antagonistic activity.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y₁₄R Antagonists with Anti-Inflammatory Characters

Wang

Zhou

et al. 2022

J. Med. Chem.

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UDPG/P2Y14R signaling pathway has been considered as a potential therapeutic target for innate immune system diseases. Based on the scaffold hopping strategy, a series of pyrazole analogues were designed and synthesized as novel P2Y14R antagonists with improved physicochemical properties, together with potential anti-inflammatory activities. Additionally, we designed and synthesized a fluorescent probe based on highly selective and potent PPTN to study the affinity of synthesized compounds. The optimized compound 16 (1-(4-fluorobenzyl)-5-(4-methylbenzamido)-1H-pyrazole-3-carboxylic acid, P2Y14R IC50 = 1.93 nM) showed strong binding ability to P2Y14R, high selectivity, notably improved solubility, and more favorable pharmacokinetic profiles. Moreover, compound 16 possessed extremely low cytotoxicity and anti-inflammatory effect in vitro. In an acute peritonitis model, compound 16 could effectively reduce the levels of inflammatory factor IL-6, IL-1β, and TNF-α of mice induced by LPS. Compound 16, with potent in vitro and in vivo efficacy and favorable druggability, can be a promising candidate for further research.

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Recent progress on the discovery of P2Y14 receptor antagonists

Cited by 21 publications

References 34 publications

Structure–activity features of purines and their receptors: implications in cell physiopathology

Structure–activity features of purines and their receptors: implications in cell physiopathology

Role of UDP-Sugar Receptor P2Y14 in Murine Osteoblasts

Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y₁₄R Antagonists with Anti-Inflammatory Characters

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Recent progress on the discovery of P2Y14 receptor antagonists

Cited by 21 publications

References 34 publications

Structure–activity features of purines and their receptors: implications in cell physiopathology

Structure–activity features of purines and their receptors: implications in cell physiopathology

Role of UDP-Sugar Receptor P2Y14 in Murine Osteoblasts

Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y14R Antagonists with Anti-Inflammatory Characters

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Discovery of a Series of 5-Amide-1H-pyrazole-3-carboxyl Derivatives as Potent P2Y₁₄R Antagonists with Anti-Inflammatory Characters