{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:46:49Z","timestamp":1785764809625,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004442","name":"National Science Centre","doi-asserted-by":"publisher","award":["OPUS 2022\/45\/B\/NZ7\/04246"],"award-info":[{"award-number":["OPUS 2022\/45\/B\/NZ7\/04246"]}],"id":[{"id":"10.13039\/501100004442","id-type":"DOI","asserted-by":"publisher"}]},{"award":["OPUS 2022\/45\/B\/NZ7\/04246"],"award-info":[{"award-number":["OPUS 2022\/45\/B\/NZ7\/04246"]}],"id":[{"id":"https:\/\/ror.org\/03ha2q922","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Histamine is a biologically active monoamine acting through four G protein-coupled receptors (H1R\u2013H4R), which represent attractive therapeutic targets for a range of diseases. Nowadays, H4R is recognized as a key player in inflammation and cancer. Here, we describe the design, syntheses and characterization of new H4R ligands containing pyrido[2,3-d]pyrimidine or pyrimidine scaffold. Candidate structures were scored in silico by docking to the structure of the human inactive H4R. Favorable structures were synthesized and, after confirmation of identity, their affinities were verified in in vitro screenings. Tested compounds did not exhibit any relevant cytotoxic (PrestoBlue) or antiproliferative (BrdU incorporation) effects at concentrations used in the functional assays. In a radioligand displacement assay (H4R affinity) the pyrimidine series showed lower binding, whereas several pyrido[2,3-d]pyrimidine derivatives and one pyrimidine analog produced &gt;60% inhibition at 1 \u00b5M. Two similar compounds with the highest and moderate affinities were selected for further studies. In the Gi\u2013cAMP pathway, both compounds behaved as moderate H4R antagonists, but in contrast, their profiles diverged in the \u03b2-arrestin pathway. These findings suggest ligand-dependent biased differences in signaling across G-protein and \u03b2-arrestin pathways at H4R. Overall, YAN-153 emerges as a promising lead structure for further optimization and for more detailed in vitro (e.g., metabolic stability, selectivity) and in vivo studies.<\/jats:p>","DOI":"10.3390\/ijms27156892","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Virtual Screening, Synthesis and In Vitro Characterization of Histamine H4 Receptor Ligands Based on Pyrimidine Scaffolds"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1067-4223","authenticated-orcid":false,"given":"Olga","family":"Michalak","sequence":"first","affiliation":[{"name":"Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, \u0141ukasiewicz Research Network-Industrial Chemistry Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-9317","authenticated-orcid":false,"given":"Marcin","family":"Cybulski","sequence":"additional","affiliation":[{"name":"Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, \u0141ukasiewicz Research Network-Industrial Chemistry Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-5887","authenticated-orcid":false,"given":"Piotr","family":"Krzeczy\u0144ski","sequence":"additional","affiliation":[{"name":"Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, \u0141ukasiewicz Research Network-Industrial Chemistry Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliwia","family":"Zegrocka-Stendel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, 1b Stefana Banacha Str., 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5701-7490","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Dutkiewicz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, 1b Stefana Banacha Str., 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4798-4062","authenticated-orcid":false,"given":"Dorota","family":"Dymkowska","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Ludwika Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1466-0742","authenticated-orcid":false,"given":"Agnieszka","family":"Olejarz-Maciej","sequence":"additional","affiliation":[{"name":"Department of Chemical Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4035-659X","authenticated-orcid":false,"given":"Tadeusz","family":"Karcz","sequence":"additional","affiliation":[{"name":"Department of Chemical Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2055-4935","authenticated-orcid":false,"given":"Mariam","family":"Dubiel","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2317-273X","authenticated-orcid":false,"given":"Pakhuri","family":"Mehta","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Kubiszewski","sequence":"additional","affiliation":[{"name":"Analytical Research Section, Pharmaceutical Analysis Laboratory, \u0141ukasiewicz Research Network\u2013Industrial Chemistry Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"Lorkowski","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5882-1029","authenticated-orcid":false,"given":"Jakub","family":"Jakowiecki","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Pasznik","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemys\u0142aw","family":"Miszta","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-1710","authenticated-orcid":false,"given":"Holger","family":"Stark","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University D\u00fcsseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0612-7646","authenticated-orcid":false,"given":"Katarzyna","family":"Koziak","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Nutrition, Centre for Preclinical Research and Technologies, Medical University of Warsaw, 1b Stefana Banacha Str., 02-097 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3147-3858","authenticated-orcid":false,"given":"S\u0142awomir","family":"Filipek","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, 1 Pasteura Str., 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/bph.14524","article-title":"Histamine Pharmacology: From Sir Henry Dale to the 21st Century","volume":"177","author":"Tiligada","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1124\/pr.114.010249","article-title":"International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors","volume":"67","author":"Panula","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0026-895X(24)12231-6","article-title":"Discovery of a Novel Member of the Histamine Receptor Family","volume":"59","author":"Nguyen","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36781","DOI":"10.1074\/jbc.M006480200","article-title":"Molecular Cloning and Characterization of a Novel Type of Histamine Receptor Preferentially Expressed in Leukocytes","volume":"275","author":"Oda","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S0026-895X(24)12230-4","article-title":"Cloning and Pharmacological Characterization of a Fourth Histamine Receptor (H4) Expressed in Bone Marrow","volume":"59","author":"Liu","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0022-3565(24)38851-2","article-title":"Cloning and Characterization of a Novel Human Histamine Receptor","volume":"296","author":"Morse","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0026-895X(24)12232-8","article-title":"Cloning, Expression, and Pharmacological Characterization of a Novel Human Histamine Receptor","volume":"59","author":"Zhu","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.ejmech.2007.07.014","article-title":"Binding Mode Analysis and Enrichment Studies on Homology Models of the Human Histamine H4 Receptor","volume":"43","author":"Kiss","year":"2008","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1476-5381.2009.00151.x","article-title":"The Role of Histamine H 4 Receptor in Immune and Inflammatory Disorders","volume":"157","author":"Zampeli","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1016\/j.bmcl.2011.11.098","article-title":"Synthesis of Novel Histamine H4 Receptor Antagonists","volume":"22","author":"Lane","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.anai.2010.08.005","article-title":"The Basics of Histamine Biology","volume":"106","author":"Lieberman","year":"2011","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Schirmer, B., and Neumann, D. (2021). The Function of the Histamine H4 Receptor in Inflammatory and Inflammation-Associated Diseases of the Gut. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116116"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1248\/bpb.30.2217","article-title":"Expression of Histamine H4 Receptor in Synovial Cells from Rheumatoid Arthritic Patients","volume":"30","author":"Ohki","year":"2007","journal-title":"Biol. Pharm. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/sj.jid.5701250","article-title":"Human Inflammatory Dendritic Epidermal Cells Express a Functional Histamine H4 Receptor","volume":"128","author":"Dijkstra","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7062","DOI":"10.4049\/jimmunol.176.11.7062","article-title":"The Histamine H4 Receptor Mediates Allergic Airway Inflammation by Regulating the Activation of CD4+ T Cells","volume":"176","author":"Dunford","year":"2006","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.lfs.2012.10.030","article-title":"Expression of the Histamine H4 Receptor in Dermal and Articular Tissues","volume":"92","author":"Yamaura","year":"2013","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nguyen, P.L., Cho, J., Nguyen, P.L., and Cho, J. (2021). Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets. Biomolecules, 11.","DOI":"10.3390\/biom11081232"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1369\/00221554221083670","article-title":"Histamine H4 Receptor Expression in Triple-Negative Breast Cancer: An Exploratory Study","volume":"70","author":"Speisky","year":"2022","journal-title":"J. Histochem. Cytochem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nicoud, M.B., Formoso, K., and Medina, V.A. (2019). Pathophysiological Role of Histamine H4 Receptor in Cancer: Therapeutic Implications. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00556"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41416-018-0173-z","article-title":"Immunomodulatory Role of Histamine H4 Receptor in Breast Cancer","volume":"120","author":"Sterle","year":"2018","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/cbdd.12431","article-title":"Histamine H4 Receptor Ligands: Future Applications and State of Art","volume":"85","author":"Fernandes","year":"2015","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_22","first-page":"462","article-title":"The Histamine H4 Receptor as a New Therapeutic Target for Inflammation","volume":"26","author":"Thurmond","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kiyohara, K., Uta, D., Nagaoka, Y., Kino, Y., Nonaka, H., Ninomiya-Baba, M., Fujita, T., Kiyohara, K., Uta, D., and Nagaoka, Y. (2022). Involvement of Histamine H3 Receptor Agonism in Premature Ejaculation Found by Studies in Rats. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042291"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/S0022-3565(25)10340-6","article-title":"S-[2-(4-Imidazolyl)Ethyl]Isothiourea, a Highly Specific and Potent Histamine H3 Receptor Agonist","volume":"263","author":"Garbarg","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6538","DOI":"10.1038\/s41467-023-42260-z","article-title":"Structural Insights into the Agonists Binding and Receptor Selectivity of Human Histamine H4 Receptor","volume":"14","author":"Im","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7186","DOI":"10.1016\/j.bmc.2009.08.059","article-title":"2,4-Diaminopyrimidines as Histamine H4 Receptor Ligands\u2014Scaffold Optimization and Pharmacological Characterization","volume":"17","author":"Sander","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6650","DOI":"10.1021\/jm060880d","article-title":"Discovery of S-(2-Guanidylethyl)-Isothiourea (VUF 8430) as a Potent Nonimidazole Histamine H4 Receptor Agonist","volume":"49","author":"Lim","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_28","first-page":"628","article-title":"The New Generation of Antihistamines: Antagonists Histamine H4 Receptor on the Way to the Clinic","volume":"12","author":"Engelhardt","year":"2009","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ejphar.2011.11.027","article-title":"INCB38579, a Novel and Potent Histamine H4 Receptor Small Molecule Antagonist with Anti-Inflammatory Pain and Anti-Pruritic Functions","volume":"675","author":"Shin","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.ejmech.2014.06.032","article-title":"Aryl-1, 3, 5-Triazine Derivatives as Histamine H4 Receptor Ligands","volume":"83","author":"Ner","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6547","DOI":"10.1021\/jm800670r","article-title":"Rotationally Constrained 2,4-Diamino-5,6-Disubstituted Pyrimidines: A New Class of Histamine H4 Receptor Antagonists with Improved Druglikeness and in Vivo Efficacy in Pain and Inflammation Models","volume":"51","author":"Cowart","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1016\/j.jaci.2018.07.047","article-title":"Efficacy and Safety of the Histamine H4 Receptor Antagonist ZPL-3893787 in Patients with Atopic Dermatitis","volume":"143","author":"Werfel","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2949","DOI":"10.1021\/acs.jmedchem.7b01855","article-title":"Discovery of a Novel Highly Selective Histamine H4 Receptor Antagonist for the Treatment of Atopic Dermatitis","volume":"61","author":"Ko","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Olejarz-Maciej, A., Mogilski, S., Karcz, T., Werner, T., Kami\u0144ska, K., Kupczyk, J., Honkisz-Orzechowska, E., Latacz, G., Stark, H., and Kie\u0107-Kononowicz, K. (2023). Trisubstituted 1,3,5-Triazines as Histamine H4 Receptor Antagonists with Promising Activity In Vivo. Molecules, 28.","DOI":"10.3390\/molecules28104199"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3390\/life10040050","article-title":"Enigmatic Histamine Receptor H4 for Potential Treatment of Multiple Inflammatory, Autoimmune, and Related Diseases","volume":"10","author":"Mehta","year":"2020","journal-title":"Life"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/164_2016_130","article-title":"Clinical Development of Histamine H4 Receptor Antagonists","volume":"241","author":"Thurmond","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"270","DOI":"10.2174\/1574893615666191219094216","article-title":"Relevance of Molecular Docking Studies in Drug Designing","volume":"15","author":"Jakhar","year":"2020","journal-title":"Curr. Bioinform."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chen, G., Seukep, A.J., Guo, M., Chen, G., Seukep, A.J., and Guo, M. (2020). Recent Advances in Molecular Docking for the Research and Discovery of Potential Marine Drugs. Mar. Drugs, 18.","DOI":"10.3390\/md18110545"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Phillips, M.A., Stewart, M.A., Woodling, D.L., and Xie, Z.-R. (2018). Has Molecular Docking Ever Brought Us a Medicine?. Molecular Docking, IntechOpen.","DOI":"10.5772\/intechopen.72898"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.sbi.2017.10.010","article-title":"Protein Structure-Based Drug Design: From Docking to Molecular Dynamics","volume":"48","author":"Caflisch","year":"2018","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.2174\/138955710793564124","article-title":"Histamine H4 Receptor: A Novel Therapeutic Target for Immune and Allergic Responses","volume":"10","author":"Bhatt","year":"2010","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.2174\/0929867323666160411143151","article-title":"Monocyclic and Fused Azines and Azoles as Histamine H4 Receptor Ligands","volume":"23","author":"Kuder","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1021\/jm7014217","article-title":"Fragment Based Design of New H4 Receptor\u2212Ligands with Anti-Inflammatory Properties in Vivo","volume":"51","author":"Smits","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7855","DOI":"10.1021\/jm800876b","article-title":"Discovery of Quinazolines as Histamine H4 Receptor Inverse Agonists Using a Scaffold Hopping Approach","volume":"51","author":"Smits","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2390","DOI":"10.1021\/jm901379s","article-title":"Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists","volume":"53","author":"Smits","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5439","DOI":"10.1021\/jm0705051","article-title":"Synthesis, Potency, and In Vivo Profiles of Quinoline Containing Histamine H3 Receptor Inverse Agonists","volume":"50","author":"Altenbach","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1016\/j.bmcl.2010.04.045","article-title":"In Vitro Studies on a Class of Quinoline Containing Histamine H3 Antagonists","volume":"20","author":"Liu","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ejphar.2010.12.033","article-title":"Receptor-Specific Functional Efficacies of Alkyl Imidazoles as Dual Histamine H3\/H4 Receptor Ligands","volume":"654","author":"Kottke","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6043","DOI":"10.1016\/j.bmcl.2006.08.117","article-title":"Identification of 2-Arylbenzimidazoles as Potent Human Histamine H4 Receptor Ligands","volume":"16","author":"Arienti","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4149","DOI":"10.1021\/jo2003715","article-title":"Solvent-Free or Low-Solvent Large-Scale Preparation of Chloropyrimidine and Analogues","volume":"76","author":"Sun","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1016\/j.bmc.2005.01.008","article-title":"Synthesis and Biological Evaluation of New Symmetrical Derivatives as Cytotoxic Agents and Apoptosis Inducers","volume":"13","author":"Cordeu","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100170","DOI":"10.1016\/j.slasd.2024.100170","article-title":"High-Throughput Kinetics in Drug Discovery","volume":"29","author":"Pinto","year":"2024","journal-title":"SLAS Discov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103760","DOI":"10.1016\/j.drudis.2023.103760","article-title":"Affinity Selection Mass Spectrometry Speeding Drug Discovery","volume":"28","author":"Prudent","year":"2023","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Roy, A., and Roy, A. (2018). Early Probe and Drug Discovery in Academia: A Minireview. High-Throughput, 7.","DOI":"10.3390\/ht7010004"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kanemaru, K., and Nakamura, Y. (2023). Activation Mechanisms and Diverse Functions of Mammalian Phospholipase C. Biomolecules, 13.","DOI":"10.3390\/biom13060915"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1124\/jpet.102.046581","article-title":"Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells","volume":"305","author":"Hofstra","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"102365","DOI":"10.1016\/j.rpth.2024.102365","article-title":"Inositol 1,3,4,5-Tetrakisphosphate: A Remarkable Second Messenger in Platelet Signaling","volume":"8","author":"Braun","year":"2024","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.molimm.2014.05.007","article-title":"Functional Characterization of Histamine H4 Receptor on Human Mast Cells","volume":"62","author":"Jemima","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"147130","DOI":"10.1016\/j.ijbiomac.2025.147130","article-title":"Diamine Oxidase Deficiency Implications for Health, Current Management, and Future Directions in the Treatment of Histamine Intolerance: A Review","volume":"327","author":"Bori","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_60","unstructured":"(2026, January 15). Jnj-7777120|C14H16ClN3O|CID 4908365\u2014PubChem, Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/4908365."},{"key":"ref_61","unstructured":"(2026, January 15). AlphaFold Protein Structure Database. Available online: https:\/\/alphafold.ebi.ac.uk\/search\/text\/Q9H3N8."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6105","DOI":"10.1038\/s41467-022-33880-y","article-title":"Structural Basis for Recognition of Antihistamine Drug by Human Histamine Receptor","volume":"13","author":"Peng","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: An Improved Force Field for Folded and Intrinsically Disordered Proteins","volume":"14","author":"Huang","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"D370","DOI":"10.1093\/nar\/gkr703","article-title":"OPM Database and PPM Web Server: Resources for Positioning of Proteins in Membranes","volume":"40","author":"Lomize","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1002\/jcc.540130805","article-title":"Settle: An Analytical Version of the SHAKE and RATTLE Algorithm for Rigid Water Models","volume":"13","author":"Miyamoto","year":"1992","journal-title":"J. Comput. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A Smooth Particle Mesh Ewald Method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1002\/prot.23106","article-title":"The VSGB 2.0 Model: A next Generation Energy Model for High Resolution Protein Structure Modeling","volume":"79","author":"Li","year":"2011","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S1043-9471(05)80049-7","article-title":"[19] Integrated Methods for the Construction of Three-Dimensional Models and Computational Probing of Structure-Function Relations in G Protein-Coupled Receptors","volume":"Volume 25","author":"Ballesteros","year":"1995","journal-title":"Methods in Neurosciences"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6892\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:01:04Z","timestamp":1785762064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6892"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":70,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156892"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156892","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}