Initial Validation of Brief Measures of Suicide Risk Factors: Common Data Elements used by the Military Suicide Research Consortium.

The Military Suicide Research Consortium (MSRC) developed a 57-item questionnaire assessing suicide risk factors, referred to as the Common Data Elements (CDEs), in order to facilitate data sharing and improve collaboration across independent studies. All studies funded by MSRC are required to include the CDEs in their assessment protocol. The CDEs include shortened measures of the following: current and past suicide risk, lethality and intent of past suicide attempts, hopelessness, thwarted belongingness, anxiety sensitivity, posttraumatic stress disorder symptoms, traumatic brain injury, insomnia, and alcohol abuse. This study aimed to evaluate the psychometric properties of the CDE items drawn from empirically validated measures. Exploratory factor analysis was used to examine the overall structure of the CDE items, and confirmatory factor analyses were used to evaluate the distinct properties of each scale. Internal consistencies of the CDE scales and correlations with full measures were also examined. Merged data from 3,140 participants (81.0% military service members, 75.6% male) across 19 MSRC-funded studies were used in analyses. Results indicated that all measures exhibited adequate internal consistency, and all CDE shortened measures were significantly correlated with the corresponding full measures with moderate to strong effect sizes. Factor analyses indicated that the shortened CDE measures performed well in comparison with the full measures. Overall, our findings suggest that the CDEs are not only brief but also provide psychometrically valid scores when assessing suicide risk and related factors that may be used in future research

Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans

2,4-Diaminopyridine d-opioid receptor agonists and their associated hERG pharmacology

A number of libraries were produced to explore the potential of 2,4-diaminopyridine lead 1. The resulting diaminopyridines proved to be potent and selective d-opioid receptor agonists. Several rounds of lead optimisation using library chemistry identified compound 17 which went on to show efficacy in an electromyography model of neuropathic pain. The structure–activity relationship of the series against the hERG ion channel proved to be a key selectivity hurdle for the series

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