1160271-34-0Relevant academic research and scientific papers
Exploration of Alternative Scaffolds for P2Y14Receptor Antagonists Containing a Biaryl Core
Jung, Young-Hwan,Yu, Jinha,Wen, Zhiwei,Salmaso, Veronica,Karcz, Tadeusz P.,Phung, Ngan B.,Chen, Zhoumou,Duca, Sierra,Bennett, John M.,Dudas, Steven,Salvemini, Daniela,Gao, Zhan-Guo,Cook, Donald N.,Jacobson, Kenneth A.
, p. 9563 - 9589 (2020/09/02)
Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y14 receptor (P2Y14R) antagonists were synthesized, and affinity was measured in P2Y14R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y14R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 ≈ 20 nM at hP2Y14R/mP2Y14R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y14R antagonist structure-activity relationship, introducing diverse physical-chemical properties.
Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor
Yu, Jinha,Ciancetta, Antonella,Dudas, Steven,Duca, Sierra,Lottermoser, Justine,Jacobson, Kenneth A.
, p. 4860 - 4882 (2018/06/20)
The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1H-1,2,3-triazol-1-yl)-5-(aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478).
A selective high-Affinity antagonist of the P2Y14 receptor inhibits udp-glucose-stimulated chemotaxis of human neutrophilss
Barrett, Matthew O.,Sesma, Juliana I.,Ball, Christopher B.,Jayasekara, P. Suresh,Jacobson, Kenneth A.,Lazarowski, Eduardo R.,Harden, T. Kendall
, p. 41 - 49 (2013/07/26)
The nucleotide-sugar-Activated P2Y14 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. (Gauthier et al., 2011) that exhibited antagonist activity at the P2Y14-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 P2Y14-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 KB of 434 pM observed. In contrast, 1 mM PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y 11, P2Y12, or P2Y13 receptors. UDP-glucose-promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-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 P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems.
Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y14
Robichaud, Jo?l,Fournier, Jean-Franois,Gagné, Sébastien,Gauthier, Jacques Yves,Hamel, Martine,Han, Yongxin,Hénault, Martin,Kargman, Stacia,Levesque, Jean-Franois,Mamane, Ya?l,Mancini, Joseph,Morin, Nicolas,Mulrooney, Erin,Wu, Jin,Black, W. Cameron
, p. 4366 - 4368 (2011/08/06)
Our series of competitive antagonists against the G-protein coupled receptor P2Y14 were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
