Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity.
View Article and Find Full Text PDFSchool communities are not immune to the alarming increase in opioid-related deaths occurring in the United States during the past decade. The purpose of this article is to share how a middle school in New York State, beginning in the late fall of 2022, successfully implemented a program to reduce the likelihood of opioid overdose deaths in their building through expansion of the accessibility of and education and training in use of naloxone, an opioid antagonist. The program is applicable for all K-12 campuses and follows the Model of Greater Awareness, Improved Training, and Increased Availability of and Accessibility to Intervention Devices, based on the steps successfully used for out-of-hospital cardiac arrest emergencies.
View Article and Find Full Text PDFA novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization.
View Article and Find Full Text PDFA series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies.
View Article and Find Full Text PDFNovel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S.
View Article and Find Full Text PDFType 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects.
View Article and Find Full Text PDFThe transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT).
View Article and Find Full Text PDFRiboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors.
View Article and Find Full Text PDFA significant improvement in agonist activity of the previously described 2-aryloctahydrophenanthrene-2,3,7-triol series of dissociated glucocorticoid receptor agonists (DAGRs) was achieved by modifying the substitution at C3 from (S)-3-hydroxy to (R)-3-hydroxy-3-methyl. The IC50 of the prototype 13 in the efficacy assay measuring repression of IL-1 induced MMP-13 expression was 3.5 nM, exhibiting 87% of the maximal effect of dexamethasone (DEX).
View Article and Find Full Text PDFA structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.
View Article and Find Full Text PDFBlood platelets are thought to be a useful peripheral model for investigating the central serotoninergic mechanisms associated with the serotonin transporter (SERT). On the other hand, an in vivo investigation of SERT in the human brain has been made possible by the development of several promising SPECT radioligands, such as [123I]-ADAM. The aim of the present study was to investigate the possible correlation between the SERT measurements in the brain and those in platelets.
View Article and Find Full Text PDFThe scope of aryl radical additions to the nitrogen of azomethines is described. Aryl, trifluoromethyl alkyl, and alpha,beta-unsaturated ketimines engage in regioselective aryl-nitrogen bond formation via 5-exo cyclizations of an aryl radical to azomethine nitrogen. Selectivity for carbon-nitrogen over carbon-carbon bond formation is generally high (>95:5) and competes only with direct aryl radical reduction by stannane (0-10%).
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