David K. Jung

The discovery of potent cRaf1 kinase inhibitors.

A series of benzylidene-1H-indol-2-one (oxindole) derivatives was synthesized and evaluated as cRaf-1 kinase inhibitors. The key features of the molecules were the donor/acceptor motif common to kinase inhibitors and a critical acidic phenol flanked by two substitutions. Diverse 5-position substitutions provided compounds with low nanomolar kinase enzyme inhibition and inhibited the intracellular MAPK pathway.

Novel Rho Kinase Inhibitors with Anti-inflammatory and Vasodilatory Activities

Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.

Short-acting benzodiazepines

council. Education and training are currently among the most important issues in the personal social services. Community care requires social workers to extend their range by adding budgetary, managerial, and coordinating responsibilities to their traditional tasks of assessment and casework. Training must also cover the knowledge and skills required for working with both children and adults and provide the ethical and legal grounding that social work needs. Two years of full time education is too short a time to establish competence across the whole range of a social workers statutory duties; the issue is not whether a third year is desirable but whether it should be spent before or after qualification. Social workers often operate in circumstances where moral values are confused and in conflict and where no single outcome is likely to satisfy all those concerned. Compulsory admission, child care, child protection, fostering and adoption, assessing risk in community and residential careall these are matters on which social workers encounter divided views on values, principles, and policy. Social work must therefore have a secure ethical basis for its professional and educational structures. Practitioners confronted by moral dilemmas and insoluble problems also need the guidance and support of a comprehensive professional organisation. Its advice and findings then form part of the bedrock of professional education. The absence of such a professional structure hampers the incorporation of ethical and technical elements into education. The proposed general council would fill this gap effectively and economically. Social works close association with local government has brought it both costs and benefits. Social workers, in a role that requires professional self-direction, are asked to function as part of the welfare bureaucracy and as front line troops performing statutory duties. But local government also provides social workers with a crucial role in protecting vulnerable people and in securing valuable services for them. It will remain a rewarding setting for the practice of social work, and social workers will continue to make an important contribution to the welfare of the community from a base in local government. The necessary condition is that they receive responsible political leadership, effective management, and proper resources. The narrow focus of statutory services now prevents social work from directly addressing the consequences of unemployment, poverty, and homelessness. A new statutory framework is required for services to adults that redirects the energies of social work to these needs and fulfils all the aspirations of community care policies. Social work should also seek to develop as a professional activity in voluntary and private agencies and in the NHS. The requirement for local authorities to meet the health services need for social work has broken down in significant areas. Health services should once again be able to employ social workers, and social work should be one of the services offered by NHS hospitals and trusts, community health services, and general practices. BILL UTTING Chairman

The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors

A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described.

Identification and structure-activity studies of novel ultrashort-acting benzodiazepine receptor agonists

The synthesis and evaluation of novel ultrashort-acting benzodiazepine (USA BZD) agonists is described. A BZD scaffold was modified by incorporation of amino acids and derivatives. The propionate side chain of glutamic acid tethers an enzymatically labile functionality where the metabolite carboxylic acid displays markedly reduced BZD receptor affinity. The USA BZDs were characterized by full agonism profiles. Copyright2000 Elsevier Science Ltd.