{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:13:37Z","timestamp":1760148817643,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Celon Pharma S.A.","award":["POIR.01.01.01-00-1341\/15"],"award-info":[{"award-number":["POIR.01.01.01-00-1341\/15"]}]},{"DOI":"10.13039\/501100005632","name":"National Centre for Research and Development \u201cNarodowe Centrum Badan i Rozwoju\u201d","doi-asserted-by":"publisher","award":["POIR.01.01.01-00-1341\/15"],"award-info":[{"award-number":["POIR.01.01.01-00-1341\/15"]}],"id":[{"id":"10.13039\/501100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Phosphoinositide 3-kinase \u03b4 (PI3K\u03b4), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-a]pyrimidine with IC50 values in the low nanomolar range and high selectivity against the PI3K\u03b4 isoform. CPL302253 (54), the most potent compound of all the structures obtained, with IC50 = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma.<\/jats:p>","DOI":"10.3390\/ph15080949","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T04:04:00Z","timestamp":1659326640000},"page":"949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3K\u03b4 Inhibitors: Part I\u2014Indole Derivatives"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4200-868X","authenticated-orcid":false,"given":"Mariola","family":"Stypik","sequence":"first","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"},{"name":"Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcin","family":"Zagozda","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6648-0604","authenticated-orcid":false,"given":"Stanis\u0142aw","family":"Micha\u0142ek","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"},{"name":"Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Dymek","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3096-8293","authenticated-orcid":false,"given":"Daria","family":"Zd\u017calik-Bielecka","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Dziachan","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Or\u0142owska","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"},{"name":"Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0239-208X","authenticated-orcid":false,"given":"Pawe\u0142","family":"Gunerka","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawe\u0142","family":"Turowski","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Hucz-Kalitowska","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Sta\u0144czak","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Sta\u0144czak","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Mulewski","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damian","family":"Smuga","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5758-9416","authenticated-orcid":false,"given":"Filip","family":"Stefaniak","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-6641","authenticated-orcid":false,"given":"Lidia","family":"Gurba-Bry\u015bkiewicz","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4462-4603","authenticated-orcid":false,"given":"Arkadiusz","family":"Leniak","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zbigniew","family":"Ochal","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-9587","authenticated-orcid":false,"given":"Mateusz","family":"Mach","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Dzwonek","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Lamparska-Przybysz","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Dubiel","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Wieczorek","sequence":"additional","affiliation":[{"name":"Celon Pharma S.A., ul. Marymoncka 15, 05-152 Kazu\u0144Nowy, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1042\/bst0310270","article-title":"PI3K-Signalling in B- and T-Cells: Insights from Gene-Targeted Mice","volume":"31","author":"Okkenhaug","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nri1056","article-title":"PI3K in Lymphocyte Development, Differentiation, and Activation","volume":"3","author":"Okkenhaug","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nri2036","article-title":"PI3K\u03b4 and PI3K\u03b3: Partners in Crime in Inflammation in Rheumatoid Arthritis and Beyond?","volume":"7","author":"Rommel","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.coph.2008.02.004","article-title":"Inhibition of PI-3 Kinase for Treating Respiratory Disease: Good Idea or Bad Idea?","volume":"8","author":"Thomas","year":"2008","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.chembiol.2010.01.010","article-title":"Discovery of Dual Inhibitors of the Immune Cell PI3Ks P110\u03b4 and P110\u03b3: A Prototype for New Anti-Inflammatory Drugs","volume":"17","author":"Williams","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4783","DOI":"10.1021\/acs.jmedchem.8b01298","article-title":"Evolution of PI3K\u03b3 and \u03b4 Inhibitors for Inflammatory and Autoimmune Diseases","volume":"62","author":"Perry","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.4049\/jimmunol.1103302","article-title":"P110\u03b4 Phosphoinositide 3-Kinase Represses IgE Switch by Potentiating BCL6 Expression","volume":"188","author":"Zhang","year":"2012","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Puri, K.D., and Gold, M.R. (2012). Selective Inhibitors of Phosphoinositide 3-Kinase Delta: Modulators of B-Cell Function with Potential for Treating Autoimmune Inflammatory Diseases and B-Cell Malignancies. Front. Immunol., 3.","DOI":"10.3389\/fimmu.2012.00256"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"544","DOI":"10.4049\/jimmunol.1400350","article-title":"Inhibition of PI3K\u03b4 Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse","volume":"193","author":"Rojas","year":"2014","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Haselmayer, P., Camps, M., Muzerelle, M., el Bawab, S., Waltzinger, C., Bruns, L., Abla, N., Polokoff, M.A., Jond-Necand, C., and Gaudet, M. (2014). Characterization of Novel PI3K\u00ce\u2019 Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00233"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.4049\/jimmunol.1101602","article-title":"Enhanced Phosphoinositide 3-Kinase \u03b4 Activity Is a Frequent Event in Systemic Lupus Erythematosus That Confers Resistance to Activation-Induced T Cell Death","volume":"187","author":"Barber","year":"2011","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8559","DOI":"10.1021\/jm300847w","article-title":"PI3K\u03b4 and PI3K\u03b3 as Targets for Autoimmune and Inflammatory Diseases","volume":"55","author":"Cushing","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1093\/rheumatology\/keq045","article-title":"Neutrophil Function in Inflammation and Inflammatory Diseases","volume":"49","author":"Wright","year":"2010","journal-title":"Rheumatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2538","DOI":"10.4049\/jimmunol.180.4.2538","article-title":"Isoform-Specific Functions of Phosphoinositide 3-Kinases: P110\u03b4 but Not P110\u03b3 Promotes Optimal Allergic Responses In Vivo","volume":"180","author":"Ali","year":"2008","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gunerka, P., Gala, K., Banach, M., Dominowski, J., Hucz-Kalitowska, J., Mulewski, K., Hajnal, A., Mikus, E.G., Smuga, D., and Zagozda, M. (2020). Preclinical Characterization of CPL302-253, a Selective Inhibitor of PI3K\u03b4, as the Candidate for the Inhalatory Treatment and Prevention of Asthma. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0236159"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nri2254","article-title":"Immunology of Asthma and Chronic Obstructive Pulmonary Disease","volume":"8","author":"Barnes","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/ni.3049","article-title":"The Immunology of Asthma","volume":"16","author":"Lambrecht","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Jeong, J.S., Kim, J.S., Kim, S.R., and Lee, Y.C. (2019). Defining Bronchial Asthma with Phosphoinositide 3-Kinase Delta Activation: Towards Endotype-Driven Management. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143525"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-3-319-91439-8_12","article-title":"Idelalisib","volume":"212","author":"Zirlik","year":"2018","journal-title":"Recent Res. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s40265-018-1013-4","article-title":"Duvelisib: First Global Approval","volume":"78","author":"Blair","year":"2018","journal-title":"Drugs"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1007\/s00277-018-3547-7","article-title":"Copanlisib, a Novel Phosphoinositide 3-Kinase Inhibitor, Combined with Carfilzomib Inhibits Multiple Myeloma Cell Proliferation","volume":"98","author":"Okabe","year":"2019","journal-title":"Ann. Hematol."},{"key":"ref_22","first-page":"821","article-title":"PI3K Inhibitors: Understanding Toxicity Mechanisms and Management","volume":"31","author":"Greenwell","year":"2017","journal-title":"Oncology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.tips.2010.04.009","article-title":"New Therapies for Asthma: Is There Any Progress?","volume":"31","author":"Barnes","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7686","DOI":"10.1021\/jm300717c","article-title":"Potent and Highly Selective Benzimidazole Inhibitors of PI3-Kinase Delta","volume":"55","author":"Murray","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4296","DOI":"10.1016\/j.bmcl.2012.05.027","article-title":"Potent and Selective Inhibitors of PI3K\u03b4: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf","volume":"22","author":"Sutherlin","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1021\/jm3003747","article-title":"Discovery of Novel PI3-Kinase \u03b4 Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition","volume":"55","author":"Safina","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.coph.2015.05.017","article-title":"PI3K inhibitors in inflammation, autoimunity and cancer","volume":"23","author":"Stark","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.cell.2006.03.035","article-title":"A Pharmacological Map of the PI3-K Family Defines a Role for P110\u03b1 in Insulin Signaling","volume":"125","author":"Knight","year":"2006","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Berndt, A., Miller, S., Williams, O., Le, D.D., Houseman, B.T., Pacold, J.I., Gorrec, F., Hon, W.-C., Ren, P., and Liu, Y. (2010). Erratum: Corrigendum: The P110\u03b4 Structure: Mechanisms for Selectivity and Potency of New PI(3)K Inhibitors. Nat. Chem. Biol., 6.","DOI":"10.1038\/nchembio0410-306a"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4815","DOI":"10.1021\/acs.jmedchem.8b01492","article-title":"Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective","volume":"62","author":"Garces","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41573-021-00209-1","article-title":"PI3K Inhibitors Are Finally Coming of Age","volume":"20","author":"Vanhaesebroeck","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1016\/j.bmcl.2007.02.032","article-title":"Synthesis and Biological Evaluation of Pyrido [3\u2032,2\u2032:4,5]Furo [3,2-d]Pyrimidine Derivatives as Novel PI3 Kinase P110\u03b1 Inhibitors","volume":"17","author":"Hayakawa","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_33","unstructured":"Kawashima, S., Matsuno, T., Yaguchi, S., Sasahara, H., and Watanabe, T. (2002). Heterocyclic Compound and Antitumor Agent Containing the Same as Active Ingredient. (U.S. Patent 1,389,617)."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5522","DOI":"10.1021\/jm800295d","article-title":"The Identification of 2-(1-H-Indazol-4-Yl)-6-(4-Methanesulfonyl-Piperazin-1-Ylmethyl)-4-Morpholin-4-Yl-Thieno [3,2-d]Pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer","volume":"51","author":"Folkes","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/cmdc.201600148","article-title":"Discovery and SAR of Novel 2,3-Dihydroimidazo [1,2-c]Quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)","volume":"11","author":"Scott","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1021\/ml200156t","article-title":"Identification of NVP-BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3 Kinase Inhibitor for Treating Cancer","volume":"2","author":"Burger","year":"2011","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7579","DOI":"10.1021\/jm2009327","article-title":"Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)\/Mammalian Target of Rapamycin (MTOR) Kinase Inhibitor (GDC-0980) for the Treatment of Cancer","volume":"54","author":"Sutherlin","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7268","DOI":"10.1021\/acs.jmedchem.6b00235","article-title":"Design, synthesis, and biological evaluation of substituted pyrimidines as potential phosphatidylinositol 3-kinase (PI3K) inhibitors","volume":"59","author":"Zhang","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_39","unstructured":"Ren, P., Liu, Y., Wilson, T.E., Chan, K., Rommel, C., and Li, L. (2009). Certain Chemical Entities, Compositions and Methods. (Patent WO2009088986)."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7381","DOI":"10.1021\/acs.jmedchem.5b00767","article-title":"Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase \u03b4 for the Treatment of Respiratory Disease","volume":"58","author":"Down","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_41","unstructured":"King-Underwood, J., Ito, K., Murray, J., Hardy, G., Brookfield, F.A., and Brown, C.J. (2011). Compounds. (Patent WO2011048111)."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9551","DOI":"10.1021\/acs.jmedchem.8b00873","article-title":"Discovery of a Novel Inhaled PI3K\u03b4 Inhibitor for the Treatment of Respiratory Diseases","volume":"61","author":"Erra","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8053","DOI":"10.1021\/acs.jmedchem.1c00434","article-title":"Discovery of AZD8154, a Dual PI3K\u03b3\u03b4 Inhibitor for the Treatment of Asthma","volume":"64","author":"Perry","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_44","unstructured":"(2022, May 31). A Study to Evaluate the Safety, Tolerability and Absorption to the Blood after Administration of Single and Multiple Doses of AZD8154 in Healthy Participants, Available online: https:\/\/clinicaltrials.gov\/show\/NCT03436316."},{"key":"ref_45","unstructured":"(2022, May 31). Dose Finding Study of Nemiralisib (GSK2269557) in Subjects with an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03345407."},{"key":"ref_46","unstructured":"(2022, May 31). Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 in Healthy Participants Who Smoke Cigarettes, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT03045887."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1182\/blood-2017-08-801191","article-title":"Effective \u201cActivated PI3K\u03b4 Syndrome\u201d\u2013Targeted Therapy with the PI3K\u03b4 Inhibitor Leniolisib","volume":"130","author":"Rao","year":"2017","journal-title":"Blood"},{"key":"ref_48","unstructured":"(2022, May 31). Study of Efficacy of CDZ173 in Patients with APDS\/PASLI, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02435173."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Sun, J., Feng, Y., Huang, Y., Zhang, S.-Q., and Xin, M. (2020). Research Advances on Selective Phosphatidylinositol 3 Kinase \u03b4 (PI3K\u03b4) Inhibitors. Bioorg. Med. Chem. Lett., 30.","DOI":"10.1016\/j.bmcl.2020.127457"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1016\/j.bmc.2014.03.036","article-title":"Structure\u2013Activity Relationship Study, Target Identification, and Pharmacological Characterization of a Small Molecular IL-12\/23 Inhibitor, APY0201","volume":"22","author":"Hayakawa","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_51","unstructured":"Michrowska-Piankowska, A., Kordes, M., Hutzler, J., Newton, T., Evans, R.R., Kreuz, K., Grossmann, K., Seitz, T., van der Kloet, A., and Witschel, M. (2013). Herbicidal Isoxazolo [5,4-b]Pyridines. (Patent WO2013104561A1)."},{"key":"ref_52","unstructured":"Moszczy\u0144ski-P\u0119tkowski, R., Bojarski, \u0141., Stefaniak, F., Wieczorek, M., Dubiel, K., and Lamparska-Przybysz, M. (2014). Pyrazolo [3,4-d]Pyrimidin-4(5h)-One Derivatives as Pde9 Inhibitors. (Patent WO2014016789A1)."},{"key":"ref_53","unstructured":"Yamada, S., Goto, T., Mashiko, T., Kogi, K., Oguchi, Y., and Narita, S. (1989). Thiazolopyridine Derivative, Their Production and Cardiovascular Treating Agents Containing Tchem. (Patent EP277701A1)."},{"key":"ref_54","unstructured":"Oakley, P., Press, N., Spanka, C., and Watson, J. (2009). Heterocyclic Compounds as Inhibitors of Cxcr2. (Patent WO2009106539A1)."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_56","unstructured":"Duzer, J., Michaelis, A., William, G., Stafford, D., Raker, J., Yu, X., Siedlecki, J., and Yang, Y. (2006). Rifamycin Analogs and Uses Thereof. (Patent US020070155715A1)."},{"key":"ref_57","unstructured":"(2022, May 31). Instant JChem. Available online: https:\/\/chemaxon.com\/products\/instant-jchem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.2133\/dmpk.22.225","article-title":"Solubility and Dissolution Profile Assessment in Drug Discovery","volume":"22","author":"Sugano","year":"2007","journal-title":"Drug Metab. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4127","DOI":"10.1016\/j.bmc.2011.05.005","article-title":"Exploratory Analysis of Kinetic Solubility Measurements of a Small Molecule Library","volume":"19","author":"Guha","year":"2011","journal-title":"Bioorg. Med. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/8\/949\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:59:42Z","timestamp":1760140782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/8\/949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,30]]},"references-count":59,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ph15080949"],"URL":"https:\/\/doi.org\/10.3390\/ph15080949","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2022,7,30]]}}}