Article
Chemistry, Medicinal
Xiaodi Zhao, Dong-Oh Yoon, Jaeho Yoo, Hyun-Ju Park
Summary: The study identified two new GPR40 agonist lead compounds, 4k and 4o, which showed promising effects in improving glycemic control and increasing plasma-active GLP-1 secretion in in vivo efficacy studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sergey O. Kuranov, Darya A. Pon'kina, Yulia V. Meshkova, Mariya K. Marenina, Mikhail V. Khvostov, Olga A. Luzina, Tatiana G. Tolstikova, Nariman F. Salakhutdinov
Summary: In this study, seven novel compounds were synthesized, which were able to activate FFAR1 and increase glucose uptake in cells without cytotoxicity. Two of these compounds showed significant hypoglycemic effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Jia-wen Xu, Xu Xu, Yun Ling, Yan-chun Wang, Yu-jie Huang, Juan-zhen Yang, Jia-ying Wang, Xu Shen
Summary: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes without cure. In this study, the therapeutic potential of vincamine (Vin), a GPR40 agonist, in ameliorating DPN-like pathology was evaluated in diabetic mice. The results showed that Vin administration improved neurological dysfunctions, blood flow velocities, blood perfusion areas, myelin sheath injury, and intraepidermal nerve fiber density impairment in DPN mice, suggesting that pharmacological activation of GPR40 could be a promising therapeutic strategy for DPN.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Medicine, Research & Experimental
Jeongwoo Park, Moo-Yeol Lee, Yoon-Seok Seo, ByeongSeok Kang, Sung-Chul Lim, Keon Wook Kang
Summary: Activation of the NLRP3 inflammasome is related to metabolic inflammation and can be suppressed by inhibiting the GPR40. TAK875 inhibits NLRP3 inflammasome activation by blocking the formation of the inflammasome component ASC. This suggests that GPR40 plays a key role in the NLRP3 inflammasome pathway.
Article
Chemistry, Medicinal
Mateusz Mach, Katarzyna Bazydlo-Guzenda, Pawel Buda, Mikolaj Matloka, Radoslaw Dzida, Filip Stelmach, Kinga Galazka, Malgorzata Wasinska-Kalwa, Damian Smuga, Dagmara Holowinska, Urszula Dawid, Lidia Gurba-Bryskiewicz, Krzysztof Wisniewski, Krzysztof Dubiel, Jerzy Pieczykolan, Maciej Wieczorek
Summary: The study focuses on the potential of the free fatty acid receptor (FFA1) for treating type 2 diabetes, but no successful agonists have entered the market yet. The discovery of CPL207280 was driven by the design for long-term safety, resulting in stable compounds with satisfactory pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Snehal N. Chaudhari, David A. Harris, Hassan Aliakbarian, James N. Luo, Matthew T. Henke, Renuka Subramaniam, Ashley H. Vernon, Ali Tavakkoli, Eric G. Sheu, A. Sloan Devlin
Summary: After bariatric surgery, levels of the endogenous bile acid cholic acid-7-sulfate (CA7S) increase in the gastrointestinal tract of both mice and humans. CA7S acts as a G-protein-coupled receptor TGR5 agonist to increase glucose tolerance during insulin resistance. This agonist remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into the circulation.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Sergio Hidalgo-Figueroa, Ana Rodriguez-Luevano, Julio C. Almanza-Perez, Abraham Giacoman-Martinez, Rolffy Ortiz-Andrade, Ismael Leon-Rivera, Gabriel Navarrete-Vazquez
Summary: The manuscript describes the design of two molecules targeting PPAR gamma and GPR40 receptors, with compound 1 showing strong activity in increasing mRNA expression levels of PPAR gamma, GLUT4, and GPR40. Additionally, compound 1 exhibited a moderate increase in insulin secretion and calcium mobilization. These findings suggest that compound 1 acts as a dual PPAR gamma and GPR40 agonist, offering better glycemic control than current treatments.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Chemistry, Medicinal
Alexey Lukin, Anna Bakholdina, Nikolay Zhurilo, Oleksandra Onopchenko, Elena Zhuravel, Sergey Zozulya, Maxim Gureev, Alexander Safrygin, Mikhail Krasavin
Summary: Three types of heterocyclic moieties were investigated as potential periphery motifs for fasiglifam, with compound 16a identified as the lead compound for further development based on its promising potential in cellular efficacy tests.
ARCHIV DER PHARMAZIE
(2021)
Article
Medicine, Research & Experimental
Gianluca Bianchini, Cecilia Nigro, Anna Sirico, Rubina Novelli, Immacolata Prevenzano, Claudia Miele, Francesco Beguinot, Andrea Aramini
Summary: New dual GPR40 and GPR120 agonist DFL23916 shows promising effects on GLP-1 secretion and glucose homeostasis, with high activity and selectivity, and potential for inducing GLP-1 secretion in vivo.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Review
Pharmacology & Pharmacy
Priyanka F. Karmokar, Nader H. Moniri
Summary: Dietary fat intake is a crucial factor in breast cancer development. Free-fatty acids (FFA) regulate carcinogenic processes through fatty acid metabolism and lipid peroxidation. The discovery of FFA receptors revealed that FFA can modulate breast cancer effects through these receptors. Abnormal FFA receptor signaling is evident in human breast carcinomas, suggesting that FFA receptors could be potential targets in breast cancer treatment.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Chemistry, Organic
Yong-Li Zhong, Yining Ji, Heather Wang, Xiao Wang, Donald R. Gauthier
Summary: A highly efficient enantioselective synthesis method was developed for the synthesis of potent G-protein-coupled receptor 40 agonist MK-2305. The key tetrasubstituted olefin was prepared through a stereoselective chemical reaction, followed by highly enantioselective rhodium-catalyzed transfer hydrogenation to obtain the target compound MK-2305 in high purity. The tethered catalysts used in the reaction showed superior reactivity, as revealed by NMR studies.
Article
Nutrition & Dietetics
Maria Dolores Rodriguez-Perez, Inmaculada Perez de Algaba, Esther Martin-Aurioles, Maria Monsalud Arrebola, Laura Ortega-Hombrados, Cristina Verdugo, Maria Africa Fernandez-Prior, Alejandra Bermudez-Oria, Jose Pedro De la Cruz, Jose Antonio Gonzalez-Correa
Summary: This study aimed to evaluate the neuroprotective effect of a polyphenol called 3',4'-dihydroxyphenylglycol (DHPG) from olive oil in a diabetes model, and whether another polyphenol called hydroxytyrosol (HT) could modify this effect. The results showed that both DHPG and HT could reduce oxidative stress, improve cell survival, and reduce retinal cell loss. The combined use of DHPG and HT had a better effect.
Article
Chemistry, Multidisciplinary
Kristin M. Sobie, Matthew Albritton, Yinuo Yang, Mariana M. Alves, Adrian Roitberg, Alexander J. Grenning
Summary: A strategy for constructing vicinal 4 degrees/3 degrees carbons via reductive Cope rearrangement is reported herein. Substrates with Cope rearrangement kinetic barriers of approximately 23 kcal mol(-1) and isoenergetic favorability (Delta G approximately 0) have been designed. These fluxional/shape-shifting molecules can be driven forward by chemoselective reduction into useful polyfunctionalized building blocks.
Review
Neurosciences
Jianheng Chen, Qian Li, Jiang Zhu, Zijing Yuan, Tao Wang, Jie Song
Summary: This study highlights the importance of the relationship between gut microbiota and immune system disorder in the neuropathology of Alzheimer's disease, providing a new direction for the treatment of AD by focusing on the advanced mechanism of inflammatory response.
NEUROTOXICITY RESEARCH
(2021)
Article
Chemistry, Organic
Weiqiang Chen, Hui-Jing Li, Mei Liu, Pi-Xian Gong, Yan-Chao Wu
Summary: The researchers have successfully synthesized difluorinated 3-oxo-N,3-diarylpropanamides with certain hypoglycemic activity using Selectfluor and water as additives. The key steps in the reaction include difluorination, imine cleavage, and amide formation. The products were confirmed by spectra and single-crystal X-ray analysis.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)