Replacement of the hydroxamic acid group in the selective HDAC8 inhibitor PCI-34051.

PCI-34051 is a valuable tool to interrogate the therapeutic effects of selective inhibition of HDAC8. However, it has not advanced to clinical trials, perhaps due to poor PK or off-target effects. We hypothesized that the presence of a hydroxamic acid (HA) group in PCI-34051 contributed to its lack of advancement.

Structure-property relationships of fluorinated carboxylic acid bioisosteres.

Fluorinated alcohols and phenols are potentially useful as bioisosteres of the carboxylic acid functional group. To enable a direct comparison of the properties of fluorinated carboxylic acid surrogates with those of other commonly used, non-fluorinated bioisosteres, we conducted a structure-property relationship (SPR) study based on matched molecular pair (MMP) analyses. A series of representative examples have been characterized by experimentally determining physicochemical properties, such as acidity (pK), lipophilicity (logD), and permeability (PAMPA).

Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury.

Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting.

Transforming the Medication Regimen Review Process Using Telemedicine to Prevent Adverse Events.

Background/objectives: Federally-mandated consultant pharmacist-conducted retrospective medication regimen reviews (MRRs) are designed to improve medication safety in nursing homes (NH). However, MRRs are potentially ineffective. A new model of care that improves access to and efficiency of consultant pharmacists is needed.

Do Zebrafish Obey Lipinski Rules?

The use of zebrafish in whole organism phenotypic assays has become a valuable strategy throughout the drug discovery process. Zebrafish assays can be used not only to screen libraries of compounds at the earliest stages but also to evaluate advanced leads for their effects on specific biological pathways or for toxicity. However, when confronted with inactivity of a compound in a zebrafish assay, there are little data that can be used to judge if the compound is truly biologically inert or inactive due to a lack of permeability into the model organism.