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. Therefore, we replaced the HA in the PCI-34051 scaffold with a series of moieties that have the potential to bind to Zn and evaluated their activity in a HDAC8 assay. Surprisingly, none of the replacements effectively mimicked the HA, and analogs lost significant potency. Evaluation of the analogs' affinity to Zn indicated that none had affinity for Zn within the same range as the HA. These studies point to the difficulty in the application of bioisosteric replacements for Zn binding motifs.

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 (pKa), lipophilicity (logD7.4), and permeability (PAMPA). The results presented can help estimate the relative changes in physicochemical properties that may be attainable by replacing the carboxylic acid functional group with fluorine containing surrogate structures.

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. Using biochemical assays, zebrafish AKI phenotypic assays, and human kidney organoid assays, we show that selective HDAC8 inhibitors can lead to efficacy in increasingly stringent models. One of these, PCI-34051, was efficacious in a rodent model of AKI, further supporting the potential for HDAC8 inhibitors and, in particular, this scaffold as a therapeutic approach to AKI.

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. The objective of this study was to determine the impact of pharmacist-led telemedicine services on reducing high-risk medication adverse drug events (ADEs) for NH residents using medication reconciliation and prospective MRR on admission plus ongoing clinical decision support alerts throughout the residents' stay. DESIGN: Quality improvement study using a stepped-wedge design comparing the novel service to usual care in a one-year evaluation from November 2016 to October 2017. SETTING: Four NHs (two urban, two suburban) in Southwestern Pennsylvania. PARTICIPANTS: All residents in the four NHs were screened. There were 2,127 residents admitted having 652 alerts in the active period. INTERVENTION: Upon admission, pharmacists conducted medication reconciliation and prospective MRR for residents and also used telemedicine for communication with cognitively-intact residents. Post-admission, pharmacists received clinical decision support alerts to conduct targeted concurrent MRRs and telemedicine. MEASUREMENT: Main outcome was incidence of high-risk medication, alert-specific ADEs. Secondary outcomes included all-cause hospitalization, 30-day readmission rates, and consultant pharmacists' recommendations. RESULTS: Consultant pharmacists provided 769 recommendations. The intervention group had a 92% lower incidence of alert-specific ADEs than usual care (9 vs 31; 0.14 vs 0.61/1,000-resident-days; adjusted incident rate ratio (AIRR) = 0.08 (95% confidence interval (CI) = 0.01-0.40]; P = .002). All-cause hospitalization was similar between groups (149 vs 138; 2.33 vs 2.70/1,000-resident-days; AIRR = 1.06 (95% CI = 0.72-1.58); P = .75), as were 30-day readmissions (110 vs 102; 1.72 vs 2.00/1,000-resident-days; AIRR = 1.21 (95% CI = 0.76-1.93); P = .42). CONCLUSIONS: This is the first evaluation of the impact of pharmacist-led patient-centered telemedicine services to manage high-risk medications during transitional care and throughout the resident's NH stay, supporting a new model of patient care.

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. While medicinal chemistry principles suggest parameters that are predictive of human oral bioavailability, cellular permeability, and even bacterial permeability, there have been no such parameters developed for zebrafish absorption. To address this question, we compiled a set of 700 compounds reported in the literature to be active in zebrafish assays, evaluated their properties, and compared them to properties derived from a set of historical drugs and a set of recently approved oral drugs. While some properties overlap, the averages and 10th and 90th percentiles of molecular weight, octanol-water partition coefficient (logP), H-bond counts, and polar surface area for zebrafish-active compounds are statistically different from those of known drugs. This analysis should be useful to scientists interpreting structure-activity relationships based on data from zebrafish assays and help to inform the translation from fish to mammals.