{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T10:26:15Z","timestamp":1779359175876,"version":"3.51.4"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Proprotein convertase subtilisin\/kexin type 9 (PCSK9) is a key drug target for the treatment of different hypercholesterolemia\u2010related diseases. A new class of small\u2010molecule inhibitors of PCSK9 transcription, characterized by a 4\u2010amino\u20102\u2010pyridone scaffold, has been recently identified by our research group. Among them, the early lead compound\n                    <jats:bold>5c<\/jats:bold>\n                    shows high in\u2009vitro potency and favorable in\u2009vivo tolerability. However, given the suboptimal in\u2009vitro metabolic stability of\n                    <jats:bold>5c<\/jats:bold>\n                    , its optimization is reported herein by modification of the predicted metabolic soft spots through chemistry\u2010driven late\u2010stage functionalization (LSF) strategies. Microsomal stability on the newly synthesized derivatives allows drawing structure\u2013metabolism relationships (SMRs) that, coupled with a thorough pharmacological investigation on HepG2 cells, leads to the identification of novel C3\u2010 and dual C3\/NHC4\u2010functionalized pyridones with improved stability and superior pharmacological profiles. Notably, compounds\n                    <jats:bold>6b<\/jats:bold>\n                    ,\n                    <jats:bold>7<\/jats:bold>\n                    , and\n                    <jats:bold>18a<\/jats:bold>\n                    emerge as the best candidates, demonstrating markedly improved metabolic stability\/PCSK9 IC\n                    <jats:sub>50<\/jats:sub>\n                    ratio and comparable or lower cytotoxicity with respect to the parent compound\n                    <jats:bold>5c<\/jats:bold>\n                    . These findings underscore the value of LSF strategies in generating optimized analogs of\n                    <jats:bold>5c<\/jats:bold>\n                    with strong potential for further preclinical development.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202500651","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T09:00:51Z","timestamp":1764320451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Optimization of 4\u2010Amino\u20102\u2010Pyridone Inhibitors of Proprotein Convertase Subtilisin\/Kexin Type 9: Integrating Structure\u2013Activity and Structure\u2013Metabolism Relationships"],"prefix":"10.1002","volume":"21","author":[{"given":"Lisa","family":"Giannessi","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Giovanna","family":"Lupo","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Padova  35128 Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Ugolotti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca","family":"Papotti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Mattina","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Grazia","family":"Martina","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Demurtas","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Padula","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Nicoli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Crescenzio","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Padova  35128 Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-7441","authenticated-orcid":false,"given":"Nicola","family":"Ferri","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Padova  35128 Padova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6665-263X","authenticated-orcid":false,"given":"Francesca","family":"Zimetti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0874-6697","authenticated-orcid":false,"given":"Marco","family":"Radi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze degli Alimenti e del Farmaco (DipALIFAR) Universit\u00e0 degli Studi di Parma  Viale delle Scienze 27\/A 43124 Parma Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0335507100"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnab035"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175721"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00530-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2911-7"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-021-00821-2"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-022-02200-y"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.11.009"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137536"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/MS9.0000000000001601"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13210"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/v15020360"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10081621"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00120"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/13872877241284213"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-0977-6"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232012192"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2023.11.008"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160411"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athplu.2024.11.003"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.116063"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8008663"},{"key":"e_1_2_8_24_1","first-page":"495","volume":"8","author":"Di L.","year":"2005","journal-title":"Curr. Opin. Drug. Discov. Devel."},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b06526"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS00380A"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac313"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4CC02473G"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.1998.tb01680.x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000134621.14315.43"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.052407"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1135"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3699"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph15010041"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2019.06.001"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.2147\/TCRM.S144121"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500651","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.202500651","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202500651","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T17:08:18Z","timestamp":1768669698000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202500651"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/cmdc.202500651"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202500651","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"assertion":[{"value":"2025-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202500651"}}