{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:34:43Z","timestamp":1762900483378,"version":"build-2065373602"},"reference-count":20,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:00:00Z","timestamp":1689552000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MCIN\/AEI\/10.13039\/501100011033","award":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"],"award-info":[{"award-number":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"]}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"],"award-info":[{"award-number":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council (CSC)","doi-asserted-by":"publisher","award":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"],"award-info":[{"award-number":["PID2020-118127RB-I00","PID2019-107991RB-100","PID2021-122116OB-I00","2021 SGR 00357","202007565030"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.<\/jats:p>","DOI":"10.3390\/molecules28145468","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T01:46:02Z","timestamp":1689644762000},"page":"5468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design and Synthesis of AMPK Activators and GDF15 Inducers"],"prefix":"10.3390","volume":"28","author":[{"given":"Meijian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Pediatric Research Institute-Hospital Sant Joan de D\u00e9u, 08950 Esplugues de Llobregat, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Bag\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4551-4825","authenticated-orcid":false,"given":"Emma","family":"Barroso","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Pediatric Research Institute-Hospital Sant Joan de D\u00e9u, 08950 Esplugues de Llobregat, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Palomer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Pediatric Research Institute-Hospital Sant Joan de D\u00e9u, 08950 Esplugues de Llobregat, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9296-6026","authenticated-orcid":false,"given":"Santiago","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9117-8239","authenticated-orcid":false,"given":"Carmen","family":"Escolano","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7138-8207","authenticated-orcid":false,"given":"Manuel","family":"V\u00e1zquez-Carrera","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"},{"name":"Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Pediatric Research Institute-Hospital Sant Joan de D\u00e9u, 08950 Esplugues de Llobregat, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/j.tem.2022.08.004","article-title":"Knocking on GDF15\u2032s door for the treatment of type 2 diabetes mellitus","volume":"33","author":"Barroso","year":"2022","journal-title":"Trends Endocrinol. 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