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Discovery of a brain-sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation
Bioorg Med Chem Lett. 2023 Mar 15;85:129237. doi: 10.1016/j.bmcl.2023.129237. Online ahead of print.ABSTRACTAtrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potass...
Source: Bioorganic and Medicinal Chemistry Letters - March 16, 2023 Category: Chemistry Authors: Stefan Peukert Hatice Belgin Gulgeze Efthymiou Ruowei Mo Yunshan Peng Fupeng Ma Guillaume Barbe Gregory Bebernitz Cary Fridrich Chiara Buono Eric T Williams Thomas Daniels Lisha Li Xia Zhang Yuichiro Adachi Mie Abe Andrew K P Taggart Source Type: research

Structure-Activity Relationship Studies of Functionalized Aromatic Peptidomimetics as Neurolysin Activators
Bioorg Med Chem Lett. 2022 Mar 12:128669. doi: 10.1016/j.bmcl.2022.128669. Online ahead of print.ABSTRACTModulating peptidase neurolysin (Nln) has been identified as a potential cerebroprotective target for the development of therapeutics for ischemic stroke. Continued structure-activity relationship studies on peptidomimetic small molecule activators of Nln bearing electron-donating and electron- withdrawing functionalized phenyls are explored. Incorporation of fluorine or trifluoromethyl groups produces Nln activators with enhanced A50, while methoxy substitution produces derivatives with enhanced Amax. Selected activato...
Source: Bioorganic and Medicinal Chemistry Letters - March 16, 2022 Category: Chemistry Authors: Md Shafikur Rahman Shiva Hadi Esfahani Saeideh Nozohouri Shikha Kumari Joanna Kocot Yong Zhang Thomas J Abbruscato Vardan T Karamyan Paul C Trippier Source Type: research

Bright Chemiluminescent Dioxetane Probes for the Detection of Gaseous Transmitter H < sub > 2 < /sub > S
Bioorg Med Chem Lett. 2021 May 28:128148. doi: 10.1016/j.bmcl.2021.128148. Online ahead of print.ABSTRACTHydrogen sulfide (H2S), the third gaseous transmitter after CO and NO, is a double-edged sword in the human body. A specific concentration of H2S can attenuate myocardial ischemia-reperfusion injury by preserving mitochondrial function, in contrast, cause illness, including inflammation and stroke. There are already some probes for the real-time monitoring of the level of H2S in the biological environment. However, they have some disadvantages, such as phototoxicity, low sensitivity, and low quantum yield. In this resea...
Source: Bioorganic and Medicinal Chemistry Letters - May 31, 2021 Category: Chemistry Authors: Zheng Zhang Yuxing Lin Zhenzhen Li Gaopan Dong Yuqi Gao Siyue Ma Jie Li Lupei Du Minyong Li Source Type: research

Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores.
We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described. PMID: 33161125 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - November 5, 2020 Category: Chemistry Authors: Liu J, Shao PP, Guiadeen D, Krikorian A, Sun W, Deng Q, Cumiskey AM, Duffy RA, Murphy BA, Mitra K, Johns DG, Duffy JL, Vachal P Tags: Bioorg Med Chem Lett Source Type: research

In vivo evaluation of 11CTMI, a COX-2 selective PET tracer, in baboons.
The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki ≤ 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2-7 (mL/cm3). We ...
Source: Bioorganic and Medicinal Chemistry Letters - October 31, 2018 Category: Chemistry Authors: Kumar JSD, Zanderigo F, Prabhakaran J, Rubin-Falcone H, Parsey RV, Mann JJ Tags: Bioorg Med Chem Lett Source Type: research

Identification and initial optimization of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB).
Abstract The discovery, synthesis and preliminary structure-activity relationship (SAR) of a novel class of inhibitors of Clostridium difficile (C. difficile) toxin B (TcdB) is described. A high throughput screening (HTS) campaign resulted in the identification of moderately active screening hits 1-5 the most potent of which was compound 1 (IC50 = 0.77 µM). In silico docking of an early analog offered suggestions for structural modification which resulted in the design and synthesis of highly potent analogs 13j(IC50 = 1 nM) and 13 l(IC50 = 7 nM) which were chosen as leads for further optimizat...
Source: Bioorganic and Medicinal Chemistry Letters - January 5, 2018 Category: Chemistry Authors: Letourneau JJ, Stroke IL, Hilbert DW, Sturzenbecker LJ, Marinelli BA, Quintero JG, Sabalski J, Ma L, Diller DJ, Stein PD, Webb ML Tags: Bioorg Med Chem Lett Source Type: research

Small molecule SUMOylation activators are novel neuroprotective agents.
Abstract Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately v...
Source: Bioorganic and Medicinal Chemistry Letters - December 13, 2017 Category: Chemistry Authors: Krajnak K, Dahl R Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of aryloxyacetamide derivatives as neuroprotective agents.
Abstract A series of new aryloxyacetamide derivatives 10a-s and 14a-m are designed and synthesized. Their protective activities against the glutamate-induced cell death were investigated in differentiated rat pheochromocytoma cells (PC12 cells). Most compounds exhibited neuroprotective effects, especially for 10m, 10r, 14b and 14c, which showed potential protection of PC12 cells at three doses (0.1, 1.0, 10μM). MTT assay, Hoechst 33342/PI double staining, and high content screening (HCS) revealed that pretreatment of the cells with 10m, 10r, 14b and 14c has significantly decreased the extent of cell apoptosis in ...
Source: Bioorganic and Medicinal Chemistry Letters - March 25, 2016 Category: Chemistry Authors: Zhong Y, Xu Y, Zhang AX, Li XF, Xu ZY, Li P, Wu B Tags: Bioorg Med Chem Lett Source Type: research

Targeted fluorescent probes for detection of oxidative stress in the mitochondria.
Abstract Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes, stroke, ischemia/reperfusion injury, age-related macular degeneration (AMD) and cancer. Recently, we developed two new mitochondria-targeting fluorescent probes, MitoProbes I/II, which specifically localize in mitochondria and employed both in vivo and in vitro for detection of mitochondrial oxidative stress. Here, we report the design and synthesis of these agents, as well as their utility for real-time imaging of mitochondrial oxidative stress in cells. PMID: 26189896 [PubMed - as supplied by publisher]
Source: Bioorganic and Medicinal Chemistry Letters - July 9, 2015 Category: Chemistry Authors: Yapici NB, Mandalapu S, Michael Gibson K, Bi L Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and positive inotropic evaluation of 1,2,4triazolo3,4-aphthalazine and tetrazolo5,1-aphthalazine derivatives bearing substituted piperazine moieties.
Abstract Four series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted piperazine moieties were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume in isolated rabbit-heart preparations. Several compounds were developed and showed favorable activities compared to the standard drug milrinone, with (4-([1,2,4]triazolo[3,4-a]phthalazin-6-yl)piperazin-1-yl)(p-tolyl)methanone (5g) being identified as the most potent with an increased stroke volume of 19.15±0.22% (milrinone: 2.46±0.07%) at a concentration of 3×10...
Source: Bioorganic and Medicinal Chemistry Letters - March 3, 2014 Category: Chemistry Authors: Ma LX, Cui BR, Wu Y, Liu JC, Cui X, Liu LP, Piao HR Tags: Bioorg Med Chem Lett Source Type: research