Heteroalicyclic carboxamidines as inhibitors of inducible nitric oxide synthase; the identification of (2R)-2-pyrrolidinecarboxamidine as a potent and selective haem-co-ordinating inhibitor.

Heteroalicyclic carboxamidines were synthesised and evaluated as inhibitors of nitric oxide synthases. (2R)-2-Pyrrolidinecarboxamidine, in particular, was shown to be a highly potent in vitro (IC(50)=0.12 µM) and selective iNOS inhibitor (>100-fold vs both eNOS and nNOS), with probable binding to the key anchoring glutamate residue and co-ordination to the haem iron.

Psychometric Evaluation of the ACHIEVE Assessment.

Objective: There has been a significant change within clinical practice in childhood disability from "treating" at the level of body function to ecological approaches that address the child's involvement in everyday life. Clinical assessment, and robust tools to support this, are of key importance. The aim of this study was to assess the psychometric properties of the ACHIEVE Assessment in a clinical dataset. The ACHIEVE assessment is a parent and teacher report of participation in home, school and community settings, important contributory factors for participation, and environmental factors. Design: ACHIEVE scores of children were collected from parents and teachers. The Rasch Rating Scale Model produced model estimates with WINSTEPS software. Setting: Clinical rehabilitation settings in Scotland (United Kingdom). Subjects: 401 parents and 335 teachers of 402 children participated resulting in a final sample of 736 responses. Children (78% male) were 4-17 years old (mean 7.91 years SD 2.61). Children had a range of disabilities including Developmental Coordination Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder. Results: The study includes a large clinical sample of children with disabilities. The results demonstrate that the ACHIEVE Assessment can provide unidimensional measurements of children's participation and important contributory factors for participation. Differential item functioning analysis indicated majority of items were comparable between parent and teacher report. Conclusions: The results confirm evidence of appropriate psychometric properties of the ACHIEVE Assessment. ACHIEVE is a comprehensive tool that enables identification of patterns and issues around participation for clinical and research purposes.

Services for children with developmental co-ordination disorder: an evaluation against best practice principles.

PURPOSE: The National Health Service in Scotland published a best practice framework to support occupational therapists and physiotherapists to deliver effective services for children with developmental co-ordination disorder (DCD); however, adherence is variable. To highlight areas for development, this study compared the care pathway within a paediatric DCD service against the NHS Scotland framework. METHODS: A partnership of researchers and clinicians based in the United Kingdom conducted a qualitative study with 37 participants (N = 13 interview participants, N = 24 workshop participants). In-depth interviews and/or workshops were used to map the DCD service against the NHS framework. Identified gaps were aligned with four key stages of the care pathway. Qualitative analysis software was used to analyse the data. RESULTS: Core principles to guide future development were identified for each phase of the pathway. These core principles related to the NHS framework and focused on issues such as involving the family, defining clear pathways and enhancing children's participation. Participants identified potential strategies for service improvement such as developing community-based interventions and information provision. CONCLUSION: Challenges when providing services for children with DCD include confusing service pathways and poor partnership working. It is, therefore, important that clinicians utilise collaborative working strategies that support children's participation. IMPLICATIONS FOR REHABILITATION: There are numerous challenges related to the implementation of best practice principles into the provision of therapy services for children with developmental coordination disorder (DCD). It is important that AHPs seek ways of engaging parents and educational professionals at all stages of the care pathway in order to ensure optimum service provision for the child. Addressing participation is an important aspect and community-based strategies may be particularly beneficial, both as a preventative activity and as an intervention approach.

Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.