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In support of the effort to begin high-dose rate 252Cf brachytherapy treatments at Tufts-New England Medical Center, the shielding capabilities of a clinical accelerator vault against the neutron and photon emissions from a 1.124 mg 252Cf source were examined. Outside the clinical accelerator vault, the fast neutron dose equivalent rate was below the lower limit of detection of a CR-39 etched track detector and below 0.14 ± 0.02 μSv h-1 with a proportional counter, which is consistent, within the uncertainties, with natural background. The photon dose equivalent rate was also measured to be below background levels (0.1 μSv h-1) using an ionisation chamber and an optically stimulated luminescence dosemeter. A Monte Carlo simulation of neutron transport through the accelerator vault was performed to validate measured values and determine the thermal-energy to low-energy neutron component. Monte Carlo results showed that the dose equivalent rate from fast neutrons was reduced by a factor of 100,000 after attenuation through the vault wall, and the thermal-energy neutron dose equivalent rate would be an additional factor of 1000 below that of the fast neutrons. Based on these findings, the shielding installed im this facility is sufficient for the use of at least 5.0 mg of 252Cf. [ABSTRACT FROM AUTHOR]

Measures adopted to prevent the spread of COVID-19 and economic shocks caused by the pandemic have affected food networks globally, including wild meat trade networks that support the livelihoods and food security of millions of people around the world. In this article, we examine how COVID-related shocks have affected the vulnerability and coping strategies of different actors along wild meat trade networks. Informed by 1,876 questionnaires carried out with wild meat hunters, traders, vendors, and consumers in Cameroon, Colombia, Democratic Republic of Congo (DRC), and Guyana, the article presents qualitative evidence as to how COVID-19 impacted different segments of society involved in wild meat trade networks. Our findings largely align with McNamara et al. (2020) and Kamogne Tagne et al.'s (2022) causal model hypothesising how the impacts of the pandemic could lead to a change in local incentives for wild meat hunting in sub-Saharan African countries. Like McNamara et al. (2020) and Kamogne Tagne et al. (2022), we find that the pandemic reduced wild meat availability for wild meat actors in urban areas while increasing reliance on wild meat for subsistence purposes in rural areas. However, we find some impact pathways to be more relevant than others, and also incorporate additional impact pathways into the existing causal model. Based on our findings, we argue that wild meat serves as an important safety net in response to shocks for some actors in wild meat trade networks. We conclude by advocating for policies and development interventions that seek to improve the safety and sustainability of wild meat trade networks and protect access to wild meat as an environmental coping strategy during times of crisis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests., Objective: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials., Methods: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments., Results: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic., Conclusions: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies., International Registered Report Identifier (irrid): DERR1-10.2196/35442., (©Jelena Curcic, Vanessa Vallejo, Jennifer Sorinas, Oleksandr Sverdlov, Jens Praestgaard, Mateusz Piksa, Mark Deurinck, Gul Erdemli, Maximilian Bügler, Ioannis Tarnanas, Nick Taptiklis, Francesca Cormack, Rebekka Anker, Fabien Massé, William Souillard-Mandar, Nathan Intrator, Lior Molcho, Erica Madero, Nicholas Bott, Mieko Chambers, Josef Tamory, Matias Shulz, Gerardo Fernandez, William Simpson, Jessica Robin, Jón G Snædal, Jang-Ho Cha, Kristin Hannesdottir. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 10.08.2022.)

Technical evaluation of swimming performance is an essential factor in preparing elite swimmers for their competitions. Inertial measurement units (IMUs) have attracted much attention recently because they can provide coaches with a detailed analysis of swimmers' performance during training. A coach can obtain a quantitative and objective evaluation from IMU. The purpose of this study was to validate the use of a new phase-based performance assessment with a single IMU worn on the sacrum during training sessions. Sixteen competitive swimmers performed five one-way front crawl trials at their maximum speed wearing an IMU on the sacrum. The coach recorded the lap time for each trial, as it remains the gold standard for swimmer's performance in competition. The measurement was carried out once a week for 10 consecutive weeks to monitor the improvement in the swimmers' performance. Meaningful progress was defined as a time decrease of at least 0.5 s over a 25 m lap. Using validated algorithms, we estimated five goal metrics from the IMU signals representing the swimmer's performance in the swimming phases (wall push-off, glide, stroke preparation, free-swimming) and in the entire lap. The results showed that the goal metrics for free-swimming phase and the entire lap predicted the swimmer's progress well (e.g., accuracy, precision, sensitivity, and specificity of 0.91, 0.89, 0.94, and 0.95 for the lap goal metric, respectively). As the goal metrics for initial phases (wall push-off, glide, stroke preparation) achieved high precision and specificity (≥0.79) in progress detection, the coach can use them for swimmers with satisfactory free-swimming phase performance and make further improvements in initial phases. Changes in the values of the goal metrics have been shown to be correlated with changes in lap time when there is meaningful progress. The results of this study show that goal metrics provided by the phase-based performance evaluation with a single IMU can help monitoring swimming progress. Average velocity of the lap can replace traditional lap time measurement, while phase-based goal metrics provide more information about the swimmer's performance in each phase. This evaluation can help the coach quantitatively monitor the swimmer's performance and train them more efficiently., Competing Interests: Author FM is employed by Gait Up S.A. Author FD is employed by Huma Therapeutics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hamidi Rad, Gremeaux, Massé, Dadashi and Aminian.)

The use of inertial measurement units (IMUs) to compute gait outputs, such as the 3D lower-limb kinematics is of huge potential, but no consensus on the procedures and algorithms exists. This study aimed at evaluating the validity of a 7-IMUs system against the optoelectronic system. Ten asymptomatic subjects were included. They wore IMUs on their feet, shanks, thighs and pelvis. The IMUs were embedded in clusters with reflective markers. Reference kinematics was computed from anatomical markers. Gait kinematics was obtained from accelerometer and gyroscope data after sensor orientation estimation and sensor-to-segment (S2S) calibration steps. The S2S calibration steps were also applied to the cluster data. IMU-based and cluster-based kinematics were compared to the reference through root mean square errors (RMSEs), centered RMSEs (after mean removal), correlation coefficients (CCs) and differences in amplitude. The mean RMSE and centered RMSE were, respectively, 7.5° and 4.0° for IMU-kinematics, and 7.9° and 3.8° for cluster-kinematics. Very good CCs were found in the sagittal plane for both IMUs and cluster-based kinematics at the hip, knee and ankle levels (CCs > 0.85). The overall mean amplitude difference was about 7°. These results reflected good accordance in our system with the reference, especially in the sagittal plane, but the presence of offsets requires caution for clinical use.

Swimming coaches provide regular timed and technical feedback to swimmers and guide them efficiently in training sessions. Due to the complexity of swimmers’ performance, which is not visible in qualitative observation, quantitative and objective performance evaluation can better assist the coach in this regard. Inertial measurement units (IMUs) are used in swimming for objective performance evaluation. In this study, we propose a new performance evaluation feedback (SmartSwim) using IMU and investigate its effects on the swimmer’s weekly progress. Measurements were conducted each week with 15 competitive swimmers for 10 weeks using a Sacrum IMU. The SmartSwim report included a comprehensive representation of performance based on goal metrics of each phase extracted from the IMU signals. The swimmers were divided into two groups: the experimental and control groups. The SmartSwim report for each swimmer in the experimental group was given to the coach, who used it to adjust the training accordingly. The results showed that the experimental group outperformed the control group when comparing each swimmer, each session and the whole sessions. At the level of each individual, more members of the experimental group showed significant downward trend of average lap time (Mann-Kendall trend test, 95% confidence level). While comparing the sessions, the experimental group showed significantly lower lap time than the control group from the sixth session onwards (p-value < 0.05 from t-test). Considering all sessions, the experimental group showed significantly higher progress, lower average lap time, and more consistent records (Mann-Whitney U test at 95% confidence level) than the control group. This study demonstrated that SmartSwim can assist coaching by quantitatively assessing swimmers’ performance, leading to more efficient training.

The rise of zoonotic disease-related public health crises has sparked calls for policy action, including calls to close wildlife markets. Yet, these calls often reflect limited understanding of where, precisely, exposure to risk occurs along wildlife and wild meat trade chains. They also threaten to negatively impact food security and livelihoods. From a public health perspective, it is important to understand the practices that shape food safety all along the trade chain, resulting in meat that is either safe to eat or managed as a potential vector of pathogens. This article uses ethnographic methods to examine the steps that lead a wild animal from the forest to the plate of an urban consumer in Yangambi and Kisangani in the Democratic Republic of Congo (DRC). Focusing on hunters, village-level consumers, transporters, market traders and urban consumers, we highlight specific practices that expose different actors involved in the trade chain to wild meat related health risks, including exposure to food borne illnesses from contaminated meat and zoonotic pathogens through direct contact with wild animals, and the local practices in place to reduce the same. We discuss interventions that could help prevent and mitigate zoonotic and food borne disease risks associated with wild meat trade chains., Competing Interests: Conflict of interestThe authors declare no conflict of interest, (© The Author(s) 2022.)

Comprehensive monitoring of performance is essential for swimmers and swimming coaches to optimize the training. Regardless of the swimming technique, the swimmer passes various swimming phases from wall to wall, including a dive into the water or wall push-off, then glide and strokes preparation and finally, swimming up to the turn. The coach focuses on improving the performance of the swimmer in each of these phases. The purpose of this study was to assess the potential of using a sacrum-worn inertial measurement unit (IMU) for performance evaluation in each swimming phase (wall push-off, glide, stroke preparation and swimming) of elite swimmers in four main swimming techniques (i.e. front crawl, breaststroke, butterfly and backstroke). Nineteen swimmers were asked to wear a sacrum IMU and swim four one-way 25 m trials in each technique, attached to a tethered speedometer and filmed by cameras in the whole lap as reference systems. Based on the literature, several goal metrics were extracted from the instantaneous velocity (e.g. average velocity per stroke cycle) and displacement (e.g. time to reach 15 m from the wall) data from a tethered speedometer for the swimming phases, each one representing the goodness of swimmer's performance. Following a novel approach, that starts from swimming bout detection and continues until detecting the swimming phases, the IMU kinematic variables in each swimming phase were extracted. The highly associated variables with the corresponding goal metrics were detected by LASSO (least absolute shrinkage and selection operator) variable selection and used for estimating the goal metrics with a linear regression model. The selected kinematic variables were relevant to the motion characteristics of each phase (e.g. selection of propulsion-related variables in wall push-off phase), providing more interpretability to the model. The estimation reached a determination coefficient (R 2 ) value more than 0.75 and a relative RMSE less than 10% for most goal metrics in all swimming techniques. The results show that a single sacrum IMU can provide a wide range of performance-related swimming kinematic variables, useful for performance evaluation in four main swimming techniques., Competing Interests: Author FM was employed by Gait Up S.A. and author FD was employed by HUMA Therapeudics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hamidi Rad, Aminian, Gremeaux, Massé and Dadashi.)

Concerns about poaching and trafficking have led conservationists to seek urgent responses to tackle the impact on wildlife. One possible solution is the militarisation of conservation, which holds potentially far-reaching consequences. It is important to engage critically with the militarisation of conservation, including identifying and reflecting on the problems it produces for wildlife, for people living with wildlife and for those tasked with implementing militarised strategies. This Perspectives piece is a first step towards synthesising the main themes in emerging critiques of militarised conservation. We identify five major themes: first, the importance of understanding how poaching is defined; second, understanding the ways that local communities experience militarised conservation; third, the experiences of rangers; fourth, how the militarisation of conservation can contribute to violence where conservation operates in the context of armed conflict; and finally how it fits in with and reflects wider political economic dynamics. Ultimately, we suggest that failure to engage more critically with militarisation risks making things worse for the people involved and lead to poor conservation outcomes in the long run.

Purpose: Upper limb assessments in children with hemiparesis rely on clinical measurements, which despite standardization are prone to error. Recently, 3D movement analysis using optoelectronic setups has been used to measure upper limb movement, but generalization is hindered by time and cost. Body worn inertial sensors may provide a simple, cost-effective alternative., Methods: We instrumented a subset of 30 participants in a mirror therapy clinical trial at baseline, post-treatment, and follow-up clinical assessments, with wireless inertial sensors positioned on the arms and trunk to monitor motion during reaching tasks., Results: Inertial sensor measurements distinguished paretic and non-paretic limbs with significant differences (P < 0.01) in movement duration, power, range of angular velocity, elevation, and smoothness (normalized jerk index and spectral arc length). Inertial sensor measurements correlated with functional clinical tests (Melbourne Assessment 2); movement duration and complexity (Higuchi fractal dimension) showed moderate to strong negative correlations with clinical measures of amplitude, accuracy, and fluency., Conclusion: Inertial sensor measurements reliably identify paresis and correlate with clinical measurements; they can therefore provide a complementary dimension of assessment in clinical practice and during clinical trials aimed at improving upper limb function.

Within the research and development environment, higher throughput, parallelized protein purification is required for numerous activities, from small scale purification of monoclonal antibodies (mAbs) and antibody fragments for in vitro and in vivo assays to process development and optimization for manufacturing. Here, we describe specific applications and associated workflows of the Protein Maker liquid handling system utilized in both of these contexts. To meet the requirements for various in vitro assays, for the identification and validation of new therapeutic targets, small quantities of large numbers of purified antibodies or antibody fragments are often required. Reducing host cell proteins (HCP) levels following capture with Protein A by evaluating various wash buffers is an example of how parallelized protein purification can be leveraged to improve a process development outcome. Stability testing under various conditions of in-process intermediates, as an example, the mAb product from a clarified harvest, requires parallelized protein purification to generate concurrent samples for downstream assays. We have found that the Protein Maker can be successfully utilized for small-to-mid scale platform purification or for process development applications to generate the necessary purified protein samples. The ability to purify and buffer exchange up to 24 samples in parallel offers a significant reduction in time and cost per sample compared to serial purification using a traditional FPLC system. By combining the Protein Maker purification system with a TECAN Freedom EVO liquid handler for automated buffer exchange we have created a new, integrated platform for a variety of protein purification and process development applications.

The instrumented Timed "Up and Go" test (iTUG) has the potential for playing an important role in providing clinically useful information regarding an individual's balance and mobility that cannot be derived from the original single-outcome Timed "Up and Go" test protocol. The purpose of this study was to determine the reliability and validity of the iTUG using body-fixed inertial sensors in people affected by stroke. For test-retest reliability analysis, 14 individuals with stroke and 25 nondisabled elderly patients were assessed. For validity analysis, an age-matched comparison of 12 patients with stroke and 12 nondisabled controls was performed. Out of the 14 computed iTUG metrics, the majority showed excellent test-retest reliability expressed by high intraclass correlation coefficients (range 0.431-0.994) together with low standard error of measurement and smallest detectable difference values. Bland-Altman plots demonstrated good agreement between two repeated measurements. Significant differences between patients with stroke and nondisabled controls were found in 9 of 14 iTUG parameters analyzed. Consequently, these results warrant the future application of the inertial sensor-based iTUG test for the assessment of physical deficits poststroke in longitudinal study designs.

The validity of spontaneous hypertensive rat (SHR) as a model of attention deficit hyperactivity disorder (ADHD) has been explored by comparing SHR with Wistar rats in a test of attention, the two-choice visual discrimination task (2-CVDT). Animals were 4-5 weeks old during the training phase of the experiment and 6-7 weeks old during the testing phase in which they were tested with D-amphetamine, a stimulant drug used for the treatment of ADHD. As compared to Wistar, SHR showed a slightly better attention performance, a slightly lower impulsivity level, and a lower general activity during the training phase, but these differences disappeared or lessened thereafter, during the testing phase. D-amphetamine (0.5, 1 mg/kg) improved attention performance in Wistar, but not in SHR, and did not modify impulsivity and activity in the two strains. In conclusion, the present study did not demonstrate that SHR represents a valid model of ADHD, since it did not show face validity regarding the behavioral symptoms of ADHD and predictive validity regarding the effect of a compound used for the treatment of ADHD. On the other hand, this study showed that the 2-CVDT may represent a suitable tool for evaluating in adolescent Wistar rats the effect on attention of compounds intended for the treatment of ADHD.

Background: Stroke survivors often suffer from mobility deficits. Current clinical evaluation methods, including questionnaires and motor function tests, cannot provide an objective measure of the patients' mobility in daily life. Physical activity performance in daily-life can be assessed using unobtrusive monitoring, for example with a single sensor module fixed on the trunk. Existing approaches based on inertial sensors have limited performance, particularly in detecting transitions between different activities and postures, due to the inherent inter-patient variability of kinematic patterns. To overcome these limitations, one possibility is to use additional information from a barometric pressure (BP) sensor., Methods: Our study aims at integrating BP and inertial sensor data into an activity classifier in order to improve the activity (sitting, standing, walking, lying) recognition and the corresponding body elevation (during climbing stairs or when taking an elevator). Taking into account the trunk elevation changes during postural transitions (sit-to-stand, stand-to-sit), we devised an event-driven activity classifier based on fuzzy-logic. Data were acquired from 12 stroke patients with impaired mobility, using a trunk-worn inertial and BP sensor. Events, including walking and lying periods and potential postural transitions, were first extracted. These events were then fed into a double-stage hierarchical Fuzzy Inference System (H-FIS). The first stage processed the events to infer activities and the second stage improved activity recognition by applying behavioral constraints. Finally, the body elevation was estimated using a pattern-enhancing algorithm applied on BP. The patients were videotaped for reference. The performance of the algorithm was estimated using the Correct Classification Rate (CCR) and F-score. The BP-based classification approach was benchmarked against a previously-published fuzzy-logic classifier (FIS-IMU) and a conventional epoch-based classifier (EPOCH)., Results: The algorithm performance for posture/activity detection, in terms of CCR was 90.4 %, with 3.3 % and 5.6 % improvements against FIS-IMU and EPOCH, respectively. The proposed classifier essentially benefits from a better recognition of standing activity (70.3 % versus 61.5 % [FIS-IMU] and 42.5 % [EPOCH]) with 98.2 % CCR for body elevation estimation., Conclusion: The monitoring and recognition of daily activities in mobility-impaired stoke patients can be significantly improved using a trunk-fixed sensor that integrates BP, inertial sensors, and an event-based activity classifier.

The cysteine protease cruzipain is essential for the viability, infectivity, and virulence of Trypanosoma cruzi, the causative agent of Chagas disease. Thus, inhibitors of cruzipain are considered promising anti-T. cruzi chemotherapeutic agents. Reversible cruzipain inhibitors containing a nitrile "warhead" were prepared and demonstrated 50% inhibitory concentrations (IC50s) as potent as 1 nM in baculovirus-generated cruzipain enzyme assays. In epimastigote and intracellular amastigote in vitro assays, the most potent compounds demonstrated antiparasitic behavior in the 5 to 10 μM IC50 range; however, trypomastigote production from the amastigote form was ∼90 to 95% inhibited at 2 μM. Two key compounds, Cz007 and Cz008, with IC50s of 1.1 and 1.8 nM, respectively, against the recombinant enzyme were tested in a murine model of acute T. cruzi infection, with oral dosing in chow for 28 days at doses from 3 to 50 mg/kg of body weight. At 3 mg/kg of Cz007 and 3 mg/kg of Cz008, the blood parasitemia areas under the concentration-time curves were 16% and 25% of the untreated group, respectively. At sacrifice, 24 days after immunosuppression with cyclophosphamide, parasite presence in blood, heart, and esophagus was evaluated. Based on negative quantitative PCR results in all three tissues, cure rates in surviving animals were 90% for Cz007 at 3 mg/kg, 78% for Cz008 at 3 mg/kg, and 71% for benznidazole, the control compound, at 50 mg/kg.

In order for wireless body area networks to meet widespread adoption, a number of security implications must be explored to promote and maintain fundamental medical ethical principles and social expectations. As a result, integration of security functionality to sensor nodes is required. Integrating security functionality to a wireless sensor node increases the size of the stored software program in program memory, the required time that the sensor's microprocessor needs to process the data and the wireless network traffic which is exchanged among sensors. This security overhead has dominant impact on the energy dissipation which is strongly related to the lifetime of the sensor, a critical aspect in wireless sensor network (WSN) technology. Strict definition of the security functionality, complete hardware model (microprocessor and radio), WBAN topology and the structure of the medium access control (MAC) frame are required for an accurate estimation of the energy that security introduces into the WBAN. In this work, we define a lightweight security scheme for WBAN, we estimate the additional energy consumption that the security scheme introduces to WBAN based on commercial available off-the-shelf hardware components (microprocessor and radio), the network topology and the MAC frame. Furthermore, we propose a new microcontroller design in order to reduce the energy consumption of the system. Experimental results and comparisons with other works are given.

A novel series of trisubstituted ureas has been identified as potent and selective mPGES-1 inhibitors. These compounds are selective over other prostanoid enzymes such as PGF synthase and TX synthase. This series of inhibitors was developed by lead optimization of a hit from an internal HTS campaign. Lead compound 42 is potent in A549 cell assay (IC(50) of 0.34 μM) and in human whole blood assay (IC(50) of 2.1 μM). An efficient and versatile one-pot strategy for the formation of ureas, involving a reductive amination, was developed to generate these inhibitors., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The trifluoroethylamine group found in cathepsin K inhibitors like odanacatib can be replaced by a difluoroethylamine group. This change increased the basicity of the nitrogen which positively impacted the log D. This translated into an improved oral bioavailability in pre-clinical species. Difluoroethylamine compounds exhibit a similar potency against cathepsin K and selectivity profile against other cathepsins when compared to trifluoroethylamine analogs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards., (Copyright (c) 2009. Published by Elsevier Ltd.)

A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Four-plate test-retest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to four-plate test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naïve and experienced mice: a benzodiazepine, diazepam that is only active in naïve mice; and a 5-HT(2A/2C) agonist, DOI that exert its anxiolytic-like effect both in naïve and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naïve and experienced mice. Diazepam had an anxiolytic-like effect in naïve mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).

Phenanthrene imidazoles 26 and 44 have been identified as novel potent, selective and orally active mPGES-1 inhibitors. These inhibitors are significantly more potent than the previously reported chlorophenanthrene imidazole 1 (MF63) with a human whole blood IC50 of 0.20 and 0.14 microM, respectively. It exhibited a significant analgesic effect in a guinea pig hyperalgesia model at oral doses as low as 14 mg/kg. Both active and selective mPGES-1 inhibitors (26 and 44) have a relatively distinct pharmacokinetic profile and are suitable for clinical development.

Cathepsin K (Cat K) degrades bone type I collagen and is a target for the pharmacological treatment of osteoporosis. Further roles for Cat K have been recently described, some of which are supported by the use of purportedly selective Cat K inhibitors in human and rodent cell-based assays. Twelve commercial and non-commercial Cat K inhibitors were profiled against a panel of purified human, rat, and mouse cysteine cathepsins and in two cell-based enzyme occupancy assays for activity against Cat K, B, and L. Ten inhibitors, including the carbohydrazide Cat K inhibitor II (Boc-Phe-Leu-NHNH-CO-NHNH-Leu-Z), the non-covalent K4b, and the epoxide NC-2300, have either little Cat K selectivity, or appear poorly cell penetrant. The amino-acetonitrile-containing inhibitors L-873724 and odanacatib show greater than 100-fold human Cat K enzyme selectivity and have similar IC(50) values against each cathepsin in cell-based and enzyme assays. The basic inhibitor balicatib has greater cellular potencies than expected on the basis of purified enzyme assays. The accumulation of [(14)C]-balicatib in fibroblasts is blocked by prior treatment of the cells with NH(4)Cl, consistent with balicatib having lysosomotropic properties. These results support the use of L-873724 and odanacatib as tools to identify novel roles for Cat K using human cell-based systems, but suggest using caution in the interpretation of studies employing the other compounds.

Amino ketone warheads were explored as alternatives to the nitrile group of a potent and selective cathepsin K inhibitor. The resulting compounds were potent and selective inhibitors of cathepsin K and these nitrile replacements had a significant effect on metabolism and pharmacokinetics.

Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.