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

Guay, Daniel; Beaulieu, Christian; Belley, Michel; Crane, Sheldon N.; DeLuca, Jeancarlo; Gareau, Yves; Hamel, Martine; Hénault, Martin; Hyjazie, Huda; Kargman, Stacia; Chan, Chi Chung; Xu, Lijing; Gordon, Robert J.; Li, Lianhai; Mamane, Yaël; Morin, Nicolas; Mancini, Joseph A.; Thérien, Michel; Tranmer, Geoffrey K.; Truong, Vouy Linh; Wang, Zhaoyin; Black, W. Cameron

doi:10.1016/j.bmcl.2011.03.084

Cited by 29 publications

(26 citation statements)

References 16 publications

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“…High-affinity competitive antagonists were developed for the P2Y 1 -R, and both competitive and noncompetitive antagonists are available for the P2Y 12 -R. However, such highly selective probes have not been available for the other subtypes of P2Y-R, and thus, the work of Black and colleagues, recently identifying potential antagonist molecules for the P2Y 14 -R, is promising Guay et al, 2011;Robichaud et al, 2011). High-throughput screens measuring small molecule-dependent inhibition of UDP-glucose-stimulated Ca 21 mobilization in P2Y 14 -R-expressing HEK cells identified dihydropyridopyrimidine (Guay et al, 2011) and naphthoic acid-containing molecules as potential P2Y 14 -R inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…High-throughput screens measuring small molecule-dependent inhibition of UDP-glucose-stimulated Ca 21 mobilization in P2Y 14 -R-expressing HEK cells identified dihydropyridopyrimidine (Guay et al, 2011) and naphthoic acid-containing molecules as potential P2Y 14 -R inhibitors. In both cases, directed synthesis led to molecules that inhibited P2Y 14 -R-promoted Ca 21 responses in the nanomolar range of concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…In both cases, directed synthesis led to molecules that inhibited P2Y 14 -R-promoted Ca 21 responses in the nanomolar range of concentrations. It was concluded on the basis of lack of inhibition of [ 3 H]UDP binding that the dihydropyridopyrimidine derivatives were noncompetitive inhibitors of the P2Y 14 -R (Guay et al, 2011). Conversely, several of the naphthoic acid derivatives, including PPTN, inhibited [ 3 H]UDP binding with apparent binding affinities in the low nanomolar range of concentrations Robichaud et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Availability of a receptor-selective antagonist for the P2Y 14 -R receptor is crucial for elucidation of the role(s) played by this signaling protein in inflammatory/immune responses. To this end, two classes of molecules recently were found by Black and colleagues to act as antagonists of the P2Y 14 -R, and these hits were structurally modified to enhance receptor affinity Guay et al, 2011;Robichaud et al, 2011). We now have studied one of these optimized compounds in detail.…”

Section: Introductionmentioning

confidence: 99%

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A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Barrett

Sesma²,

Ball³

et al. 2013

Molecular Pharmacology

128

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The nucleotide-sugar-activated P2Y 14 receptor (P2Y 14 -R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. ) that exhibited antagonist activity at the P2Y 14 -R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y 14 -R was shifted to the right in a concentration-dependent manner by PPTN.Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a K B of 434 pM observed. In contrast, 1 mM PPTN exhibited no agonist or antagonist effect at the P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , or P2Y 13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the K B determined with recombinant P2Y 14 -R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose-promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y 14 -R that is useful for interrogating the action of this receptor in physiologic systems.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

Barrett

Sesma²,

Ball³

et al. 2013

Molecular Pharmacology

128

View full text Add to dashboard Cite

show abstract

“…Black and coworkers applied high-throughput screens to identify dihydropyridopyrimidine (Guay et al, 2011) and naphthoic acid Robichaud et al, 2011). Problems with high-affinity binding to serum proteins observed with several of these naphthoic acid analogs were partially circumvented in the analog PPTN [4-((piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid] that retained activity as a P2Y 14 R antagonist.…”

Section: Mechanisms Of Release and Metabolism Of Nucleotide Sugarsmentioning

confidence: 99%

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

Lazarowski

Harden

2015

Molecular Pharmacology

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UDP-sugars, which are indispensable for protein glycosylation reactions in cellular secretory pathways, also act as important extracellular signaling molecules. We discuss here the broadly expressed P2Y 14 receptor, a G-protein-coupled receptor targeted by UDP sugars, and the increasingly diverse set of physiologic responses discovered recently functioning downstream of this receptor in many epithelia as well as in immune, inflammatory, and other cells.

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Synthesis and antitumor evaluation of novel 4‐anilino‐7,8‐dihydropyrido[4,3‐d]pyrimidine‐6(5H)‐carboxylate derivatives as potential EGFR inhibitors

Zhang

Yan

Jin

et al. 2018

Archiv der Pharmazie

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Novel series of 4-anilino-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylates (5a-p, 7, and 8a-e) were synthesized and evaluated for their antiproliferative activity against the A549, HT29, H460, and H1975 cancer cell lines in vitro. Nine compounds (5a-c, 5i, 5j, 7, 8a, 8b, 8i) demonstrated moderate to significant cytotoxic activity with IC values below 18 µM on A549 cells, which were comparable to that of the reference gefitinib (IC = 18.44 µM). Especially, the further enzymatic analysis on epidermal growth factor receptor (EGFR), HER2, and VEGFR identified compound 5a as a promising hit that exhibited considerable potency both in cellular (IC = 5.67, 17.04, 11.29, and 12.65 µM, respectively) and EGFR enzymatic assays (IC = 14.8 nM). Compound 5a was capable of down-regulating the expression of EGFR and inhibited EGFR phosphorylation in a dose-dependent manner, representing a potential EGFR candidate for further optimization.

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

Cited by 29 publications

References 16 publications

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

A Selective High-Affinity Antagonist of the P2Y14 Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

Synthesis and antitumor evaluation of novel 4‐anilino‐7,8‐dihydropyrido[4,3‐d]pyrimidine‐6(5H)‐carboxylate derivatives as potential EGFR inhibitors

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