{"doi":"10.1021/acsptsci.4c00489","title":"Chimeras Derived from a P2Y<sub>14</sub> Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation","abstract":"Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y 14 receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y 14 R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y 14 R binding, suggesting that an optimal affinity (IC 50, nM) in the piperidine series was achieved for triazolyl N -linked glucose conjugates having one ( 8a, MRS4872, 3.21) or two ( 7a, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y 14 R affinity (IC 50, nM) was achieved with N -linked glycosides of fucose 10f (6.19) and lactose 10h (1.88), and C -linked glucose 11a (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y 14 R antagonists. Two glycoconjugates that lacked a piperidine moiety, N -linked glucose derivative 10a and the isomeric C -linked glucose derivative 11a, were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate 7a of intermediate linker length and corresponding glucuronide 7b (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y 14 R antagonists having substantial in vitro and in vivo activity.","journal":"ACS Pharmacology & Translational Science","year":2024,"id":445590,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":874585,"name":"Asmita Pramanik","orcid":null,"position":1,"is_corresponding":false},{"id":908359,"name":"Sarah A. Lewicki","orcid":"0009-0008-7449-5065","position":2,"is_corresponding":false},{"id":471638,"name":"Kwan‐Young Jung","orcid":"0000-0002-5631-8814","position":3,"is_corresponding":false},{"id":504396,"name":"Zhan-Guo Gao","orcid":"0009-0006-4777-8647","position":4,"is_corresponding":false},{"id":745501,"name":"John C.R. Randle","orcid":null,"position":5,"is_corresponding":false},{"id":199744,"name":"S. Breton","orcid":"0000-0001-6380-8689","position":6,"is_corresponding":false},{"id":287070,"name":"Zhoumou Chen","orcid":null,"position":7,"is_corresponding":false},{"id":402200,"name":"Gregory S. Whitehead","orcid":"0000-0003-3654-6446","position":8,"is_corresponding":false},{"id":285149,"name":"Daniela Salvemini","orcid":"0000-0002-0612-4448","position":9,"is_corresponding":false},{"id":305243,"name":"Donald N. Cook","orcid":"0000-0002-0052-3755","position":10,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":11,"is_corresponding":false},{"id":476636,"name":"Zhiwei Wen","orcid":"0000-0002-0821-1369","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:01:46.243344Z","pmid":"39421658","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}