{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:26:09Z","timestamp":1761863169607},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,6,12]],"date-time":"2013-06-12T00:00:00Z","timestamp":1370995200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Small molecule glucokinase activators (<jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content>) have been associated with potent antidiabetic efficacy and hepatic steatosis in rodents. This study reports the discovery of <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 50131 and <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 51434, two novel <jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content> with an original scaffold and an atypical pharmacological profile.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Activity of the compounds was assessed i<jats:italic>n vitro<\/jats:italic> by measuring activation of recombinant glucokinase, stimulation of glycogen synthesis in rat hepatocytes and increased insulin secretion from rat pancreatic islets of <jats:styled-content style=\"fixed-case\">L<\/jats:styled-content>angerhans. Efficacy and safety <jats:italic>in vivo<\/jats:italic> were evaluated after oral administration in <jats:italic>db\/db<\/jats:italic> mice by measuring glycaemia, <jats:styled-content style=\"fixed-case\">HbA1c<\/jats:styled-content> and dyslipidaemia\u2010associated events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 50131 and <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 51434 activated <jats:styled-content style=\"fixed-case\">GK<\/jats:styled-content> and stimulated glycogen synthesis in hepatocytes and insulin secretion from pancreatic islets. Unexpectedly, while both compounds effectively lowered glycaemia after acute oral administration, they did not decrease <jats:styled-content style=\"fixed-case\">HbA1c<\/jats:styled-content> after a 4\u2010week treatment in <jats:italic>db\/db<\/jats:italic> mice. This lack of antidiabetic efficacy was associated with increased plasma free fatty acids (<jats:styled-content style=\"fixed-case\">FFAs<\/jats:styled-content>), contrasting with the effect of <jats:styled-content style=\"fixed-case\">GKA<\/jats:styled-content>50 and <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>00236460, two <jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content> with sustained <jats:styled-content style=\"fixed-case\">HbA1c<\/jats:styled-content> lowering activity but neutral regarding plasma <jats:styled-content style=\"fixed-case\">FFAs<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 50131, but not <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content> 51434, also induced hepatic steatosis, as did <jats:styled-content style=\"fixed-case\">GKA<\/jats:styled-content>50 and <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>00236460. However, a shorter, 4\u2010day treatment resulted in increased hepatic triglycerides without changing the plasma <jats:styled-content style=\"fixed-case\">FFA<\/jats:styled-content> levels, demonstrating dynamic alterations in the lipid profile over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>In addition to confirming the occurrence of dyslipidaemia with <jats:styled-content style=\"fixed-case\">GKAs<\/jats:styled-content>, these findings provide new insights into understanding how such compounds may sustain or lose efficacy over time.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12172","type":"journal-article","created":{"date-parts":[[2013,3,14]],"date-time":"2013-03-14T21:03:34Z","timestamp":1363295014000},"page":"999-1010","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp>S<\/scp> 50131 and <scp>S<\/scp> 51434, two novel small molecule glucokinase activators, lack chronic efficacy despite potent acute antihyperglycaemic activity in diabetic mice"],"prefix":"10.1111","volume":"169","author":[{"given":"Fr\u00e9d\u00e9ric","family":"De Ceuninck","sequence":"first","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Kargar","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Charton","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Solo","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Perron\u2010Sierra","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Ilic","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Caliez","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean\u2010Olivier","family":"Rolin","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjorie","family":"Sadlo","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Harley","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9dric","family":"Vinson","sequence":"additional","affiliation":[{"name":"Biopharmaceutical coordination Technologie Servier  Orl\u00e9ans France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Ktorza","sequence":"additional","affiliation":[{"name":"Department of Metabolic Diseases Institut de Recherches Servier  Suresnes France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,6,12]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1470"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm900839k"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0928-0987(00)00165-2"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1042\/bj1740603","article-title":"Phosphorylation of glucose in isolated rat hepatocytes. Sigmoidal kinetics explained by the activity of glucokinase alone","volume":"15","author":"Bontemps F","year":"1978","journal-title":"Biochem J"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.3.535"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2006.06.002"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706848"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02184.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0377"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111133"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1244-z"},{"key":"e_1_2_8_13_1","first-page":"237","article-title":"Prevalence of hypertension among diabetic patients and its relation to vascular risk. Diabetes Hypertension Study Group","volume":"5","author":"Fuller H","year":"1991","journal-title":"J Hum Hypertens"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0646-8"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.9.2433"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084073"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-002-0881-y"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-002-1009-0"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2004.02.005"},{"key":"e_1_2_8_20_1","first-page":"1127","volume-title":"Methods of Enzymatic Analysis","author":"Keppler D","year":"1974"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00872.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2005.07.003"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00873.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2006.02.022"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.39.6.647"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmr.5610020301"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-1200"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.10.2022"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2010.04.054"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-2017"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm2014887"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M610094200"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI34275"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02201.x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24806"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm3008689"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1142358"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.1.1"},{"key":"e_1_2_8_39_1","first-page":"29","volume-title":"Methods in Cell Biology","author":"Seglen PO","year":"1976"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.16.2.434"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60207-9"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.43.30864"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabet.2010.10.001"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003319"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2007.02285.x"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2011.05.009"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012102522787"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbph.12172","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.12172","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T02:52:47Z","timestamp":1697424767000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.12172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,12]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1111\/bph.12172"],"URL":"https:\/\/doi.org\/10.1111\/bph.12172","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,12]]},"assertion":[{"value":"2012-11-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-03-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2013-06-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}