دورية أكاديمية
Development of Novel N -Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.
| العنوان: | Development of Novel N -Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group. |
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| المؤلفون: | Jiang Z; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Hu YT; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Guo SY; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Li YX; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Zhao DD; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Wei LY; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Lin YW; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Xu SM; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Huang SL; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Li Q; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Tan JH; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Rao Y; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Chen SB; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China., Huang ZS; School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 12439-12458. Date of Electronic Publication: 2024 Jul 12. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Anti-Obesity Agents*/pharmacology , Anti-Obesity Agents*/chemical synthesis , Anti-Obesity Agents*/pharmacokinetics , Anti-Obesity Agents*/therapeutic use , Anti-Obesity Agents*/chemistry , Hydrazones*/pharmacology , Hydrazones*/chemistry , Hydrazones*/chemical synthesis , Hydrazones*/pharmacokinetics , Hydrazones*/therapeutic use , Aldehydes*/chemistry , Obesity*/drug therapy, Animals ; Mice ; Structure-Activity Relationship ; Male ; Mice, Inbred C57BL ; Diet, High-Fat/adverse effects ; Humans ; Mice, Obese ; Molecular Structure |
| مستخلص: | The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d , featuring an 8a- N -acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3 , but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N -acylhydrazone to enhance drug-like properties. |
| المشرفين على المادة: | 0 (Anti-Obesity Agents) 0 (Hydrazones) 0 (Aldehydes) |
| تواريخ الأحداث: | Date Created: 20240712 Date Completed: 20240725 Latest Revision: 20240729 |
| رمز التحديث: | 20240730 |
| DOI: | 10.1021/acs.jmedchem.4c01242 |
| PMID: | 38996004 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.4c01242 |