Istvan Kaldor

Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064.

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.

Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors

A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2-fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states.

Discovery of a Highly Potent, Nonabsorbable Apical Sodium-Dependent Bile Acid Transporter Inhibitor (GSK2330672) for Treatment of Type 2 Diabetes

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

ABSTRACT Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC50s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC50s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC50s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

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

Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38.

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.

Relating the structure, activity, and physical properties of ultrashort-acting benzodiazepine receptor agonists.

The ultrashort-acting benzodiazepine (USA BZD) agonists reported previously have been structurally modified to improve aqueous solubility. Lactam-to-amidine modifications, replacement of the C5-haloaryl ring, and annulation of heterocycles are presented. These analogues retain BZD receptor potency and full agonism profiles.

Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists.

The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs.

A CONVENIENT SYNTHESIS OF THIOFIBRATE ANALOGS FROM ARYL SULFONYL CHLORIDES

An expedient synthesis of pharmacologically relevant thioisobutyric acid esters from aryl sulfonyl chlorides is described.