A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen.
Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico sim...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5072725?pdf=render |
| _version_ | 1818273884625960960 |
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| author | Kenji Sugawara Kohei Honda Yoshie Reien Norihide Yokoi Chihiro Seki Harumi Takahashi Kohtaro Minami Ichiro Mori Akio Matsumoto Haruaki Nakaya Susumu Seino |
| author_facet | Kenji Sugawara Kohei Honda Yoshie Reien Norihide Yokoi Chihiro Seki Harumi Takahashi Kohtaro Minami Ichiro Mori Akio Matsumoto Haruaki Nakaya Susumu Seino |
| author_sort | Kenji Sugawara |
| collection | DOAJ |
| description | Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent. |
| first_indexed | 2024-12-12T22:05:03Z |
| format | Article |
| id | doaj.art-8b7165e325904720a9d9f9b18e168d3f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T22:05:03Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8b7165e325904720a9d9f9b18e168d3f2022-12-22T00:10:24ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-011110e016478510.1371/journal.pone.0164785A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen.Kenji SugawaraKohei HondaYoshie ReienNorihide YokoiChihiro SekiHarumi TakahashiKohtaro MinamiIchiro MoriAkio MatsumotoHaruaki NakayaSusumu SeinoInsulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue. DSC108 increased the intracellular Ca2+ level in MIN6-K8 cells. Competitive inhibition experiment and electrophysiological analysis revealed sulfonylurea receptor 1 (SUR1) to be the target of DSC108 and that this diphenylthiosemicarbazide directly inhibits ATP-sensitive K+ (KATP) channels. Pharmacokinetic analysis showed that DSC108 has a short half-life in vivo. Oral administration of DSC108 significantly suppressed the rises in blood glucose levels after glucose load in wild-type mice and improved glucose tolerance in the Goto-Kakizaki (GK) rat, a model of type 2 diabetes with impaired insulin secretion. Our data indicate that DSC108 is a novel insulin secretagogue, and is a lead compound for development of a new anti-diabetic agent.http://europepmc.org/articles/PMC5072725?pdf=render |
| spellingShingle | Kenji Sugawara Kohei Honda Yoshie Reien Norihide Yokoi Chihiro Seki Harumi Takahashi Kohtaro Minami Ichiro Mori Akio Matsumoto Haruaki Nakaya Susumu Seino A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. PLoS ONE |
| title | A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. |
| title_full | A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. |
| title_fullStr | A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. |
| title_full_unstemmed | A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. |
| title_short | A Novel Diphenylthiosemicarbazide Is a Potential Insulin Secretagogue for Anti-Diabetic Agen. |
| title_sort | novel diphenylthiosemicarbazide is a potential insulin secretagogue for anti diabetic agen |
| url | http://europepmc.org/articles/PMC5072725?pdf=render |
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