Departments of Medicinal Chemistry and Diabetes Research, Merck Research Laboratories , 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States.
Published: June 2014
AI Article Synopsis
Article Abstract
A novel class of small-molecule, highly potent, and subtype-selective somatostatin SST3 agonists was discovered through modification of a SST3 antagonist. As an example, (1R,2S)-9 demonstrated not only potent in vitro SST3 agonist activity but also in vivo SST3 agonist activity in a mouse oral glucose tolerance test (OGTT). These agonists may be useful reagents for studying the physiological roles of the SST3 receptor and may potentially be useful as therapeutic agents.
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
* A new β-carboline compound was developed as a potent inhibitor of SIRT6, showing significant selectivity and deacetylase activity reduction, with further modifications leading to enhanced efficacy.
* This SIRT6 inhibitor not only reduced breast cancer cell growth, migration, and invasion but also induced apoptosis, indicating its potential as a viable treatment strategy targeting SIRT6 in breast cancer therapy.
Rigidified nucleoside derivatives with (N)-methanocarba replacement of ribose have been repurposed as peripheral subtype-selective 5-HT serotonin receptor antagonists for heart and lung fibrosis and intestinal/vascular conditions. 4'-Cyano derivative (MRS8209; , 4.27 nM) was 47-fold (human binding, but not rat and mouse) and 724-fold (functionally) selective at 5-HTR, compared to antitarget 5-HTR, and predicted to form a stable receptor complex using docking and molecular dynamics.
Class I histone deacetylases (HDACs) are considered promising targets in current cancer research. To obtain subtype-selective and potent HDAC inhibitors, we used the aminobenzamide scaffold as the zinc-binding group and prepared new derivatives with a pyrazole ring as the linking group. The synthesized compounds were analyzed in vitro using an enzymatic assay against HDAC1, -2, and -3.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China. Electronic address:
Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3.
Estrogen receptors are essential pharmacological targets for treating hormonal disorders and estrogen-dependent malignancies. Selective activation of estrogen receptor (ER) β is hypothesized to provide therapeutic benefit with reduced risk of unwanted estrogenic side-effects associated with ERα activity. However, activating ERβ without activating α is challenging due to the high sequence and structural homology between the receptor subtypes.
