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The objective of this Letter is to report the first (to our knowledge) in vivo proof of concept for a sulfenamide prodrug to orally deliver a poorly soluble drug containing a weakly-acidic NH–acid from a conventional solid dosage formulation. This proof of concept was established using BMS–708163 (1), a gamma secretase inhibitor containing a weakly acidic primary amide NH-acid as the chemical handle for attaching a series of thiol-based promoieties via a sulfenamide linkage. Aqueous stabilities and solubilities are reported for a series of six sulfenamide prodrugs (2–7) of 1. The sulfenamide prodrug containing the cysteine methyl ester promoiety (5) was chosen for a orally-dosed PK study in male beagle dog comparing a solubilized formulation of 1 against a solid dosage form of 5 in a cross-over fashion at an equivalent molar dose of 3 mg/kg. Prodrug 5 delivered essentially a superimposable PK profile of 1 compared to the solubilized formulation of 1, without any detectable exposure of 5 in systemic circulation.

The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of 1c (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT3A receptor (>300-fold). In vivo activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials.

The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

Background Healthcare settings have traditionally focused on developing safe systems by learning from incidents and errors (Kelly, Blake & Plunkett, 2016). Considerable time and energy is spent on activities including incident reporting and root cause analysis, whilst less attention is paid to the majority of times when things go well (NHS England, 2015). Birmingham St Mary’s Hospice introduced a system of Learning from Excellence (https://learningfromexcellence.com/) to address this. We hypothesised that this would improve staff morale and retention, provide evidence of good practice for team learning, quality reports and marketing and be useful for team appraisal and revalidation. Aim To institute a learning from excellence scheme within the hospice setting, across all hospice teams. We describe the set up process and support needs for this project. Method Support was obtained from the executive team. A small task and finish group was set up. Having accepted advice from other local healthcare providers, a simple form was generated. An IT apprentice supported the team to generate an electronic version of the form which was intranet based. A paper version was used where preferred. A volunteer was recruited to support the initiative. A soft launch was conducted and forms invited with the task and finish group encouraged to role model by reporting. Initially all reports were overseen by a consultant in palliative medicine, with anticipated handover to volunteer and administrative team. Recipients were provided with a response on headed notepaper to allow use in appraisal. Results Forms have been analysed and themes generated. Informal feedback has been sought from staff who have completed and received LfE reports. Conclusions Learning from excellence has been a positive experience, allowing us to focus on what is done well within the hospice setting. Some aspects of set up have been novel within our hospice and we recommend more widespread use within hospices.

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer's disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.

A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4′H-4-azaspiro[bicyclo[2.2.2]octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.

We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation and provided a diverse set of fused 6,5-heteroaryl analogs. Two potent and selective α7 nAChR partial agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20) and (1′S,3′R,4′S)-N-(7-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (21), were identified. Both agonists improved cognition in a preclinical rodent model of learning and memory. Additionally, 5-HT3A receptor SAR suggested the presence of a steric site that when engaged led to significant loss of affinity at that receptor.

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.

Changes in the prevalence of oral diseases and the funding of National Health Service Dentistry in the United Kingdom have combined to emphasize the role of the dental team in the prevention of disease. As part of this, oral health promotion plays a vital role in local communities and educational settings. Like many other inner-city London boroughs, Lambeth, Southwark and Lewisham have linguistically and culturally diverse populations, accompanied in recent years by an increasing demand and need for oral health promotion for non English speakers and those with low English language proficiency. Using the population of Lambeth, Southwark and Lewisham as an example, this paper will highlight the complexity of developing oral health promotion resources for non-English-speaking populations, where language is a barrier to accessing information and services. Practical strategies for delivering health promotion in the community will also be considered.

A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC 50 of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.

Structure–activity studies around the urea linkage in BMS-193885 ( 4a ) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y 1 receptor antagonists. In comparison to urea 4a ( K i =3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y 1 receptor ( K i =5.1 nM) and full functional antagonism ( K b =2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

NADPH-supported lipid peroxidation monitored by malondialdehyde (MDA) production in the presence of ferric pyrophosphate in liver microsomes was inactivated by heat treatment or by trypsin and the activity was not restored by the addition of purified NADPH-cytochrome P450 reductase (F PT ). The activity was differentially solubilized by sodium cholate from microsomes, and the fraction solubilized between 0.4 and 1.2% sodium cholate was applied to a Sephadex G-150 column and sub fractionated into three pools, A, B, and C. MDA production was reconstituted by the addition of microsomal lipids and F PT to specific fractions from the column, in the presence of ferric pyrophosphate and NADPH. Pool B, after removal of endogenous F PT , was highly active in catalyzing MDA production and the disappearance of arachidonate and docosahexaenoate, and this activity was abolished by heat treatment and trypsin digestion, but not by carbon monoxide. The rate of NADPH-supported lipid peroxidation in the reconstituted system containing fractions pooled from Sephadex G-150 columns was not related to the content of cytochrome P450. p -Bromo-phenylacylbromide, a phospholipase A 2 inhibitor, inhibited NADPH-supported lipid peroxidation in both liver microsomes and the reconstituted system, but did not block the peroxidation of microsomal lipid promoted by iron-ascorbate or ABAP systems. Another phospholipase A 2 inhibitor, mepacrine, poorly inhibited both microsomal and pool-B′-promoted lipid peroxidation, but did block both iron-ascorbate-driven and ABAP-promoted lipid peroxidation. The phospholipase A 2 inhibitor chlorpromazine, which can serve as a free radical quencher, blocked lipid peroxidation in all systems. The data presented are consistent with the existence of a heat-labile protein-containing factor in liver microsomes which promotes lipid peroxidation and is not F PT , cytochrome P450, or phospholipase A 2 .

We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.

Aim The aim of this research was to identify short-term career aspirations and goals of final-year dental students at a London dental school and the perceived factors that influenced these aspirations. Methods Two methods were used to collect data on final-year students’ short-term career plans and influences. Qualitative data were collected through focus groups and analysed using ‘framework methodology’. These findings informed a questionnaire survey of all students at the end of their final undergraduate year. Data were entered into and analysed using a statistical software package. Results Thirty-five students participated in focus groups, with recruitment continuing until data were saturated. Ninety per cent (n=126) of the total population (140) responded to the questionnaire survey; the majority were Asian (70%), female (58%), and aged 23 years (59%). Short-term professional expectations focused around ‘achieving professional status within a social context’, ‘gaining professional experience’, ‘developing independence’ and ‘achieving financial stability’. ‘Achieving financial stability’ was ranked as the most important influence in decision-making about their career in the short term (77%), followed by ‘balance of work and other aspects of life’ (75%) and ‘good lifestyle’ (75%). Four out of ten intended to work towards membership of a Royal College and/or becoming a specialist. Proximity to family (81%) and friends (79%) was an important or very important influence on location in the short term. Asian students were significantly more likely to rate ‘proximity to family’ ( p=0.042), working in an ‘urban area’ ( p=0.001) and ‘opportunities for private care’ ( p=0.043) of greater importance than their White counterparts. Conclusions Short-term aspirations involve ‘achieving professional status within a social context’, and personal, social, professional and financial goals. Location of future practice was significantly associated with ethnicity.

Background: Given the changing nature of the dental workforce, and the need to retain the services of future members, it is important to understand why current dental students perceive that they were motivated to study dentistry. Qualitative research provides the opportunity to explore the underlying issues in addition to informing subsequent quantitative research. The objectives of this research were to investigate final-year dental students’ motivation for studying dentistry and how they perceive this has been modified during their undergraduate degree programme. Methods: Purposive sampling of a representative group of 35 final-year dental students at King’s College London Dental Institute to participate in audio-taped focus groups. Qualitative data were analysed using Framework Methodology. Results: The findings suggest a strong emphasis on having a career, providing ‘professional status’, ‘financial benefits’, ‘job security, flexibility and independence’ and ‘good quality of life’. Students reported being attracted by features of the job, supported to a greater or lesser extent by personal experience, family and friends. It appears however that students’ initial motivation is being tempered by their experiences during their undergraduate degree programme, in particular, the ‘responsibilities of an intensive professional education’, their ‘mounting student debt’ and the perception of ‘feeling undervalued’. This perception related to dentistry in general and National Health Service dentistry in particular, being undervalued, by government, patients, the public and members of the dental profession. Conclusions: Students’ vision of a ‘contained professional career’ within health care, providing status and financial benefits, appears to have influenced their choice of dentistry. Pressures relating to student life and policy changes are perceived as impacting on key components of professional life, particularly status in the social and economic order. The implications for educators, professional leaders and policy makers are explored.

Background New graduates in the UK presently spend one year in training as Vocational Dental Practitioners (VDPs) in preparation for primary dental care. There is a growing recognition that the emerging workforce has very different professional expectations to those of earlier generations, with implications for the profession, patients and the performance of health systems. The objectives of this study were to investigate why VDPs' in England and Wales perceive they chose dentistry as a professional career; how they perceive their vision has changed and the implications for their professional career plans, both short- and longterm. Methods Purposive sampling of schemes was undertaken to include urban, rural and metropolitan schemes, schemes in areas with and without dental schools and geographic coverage across England and Wales. All VDPs in these schemes were initiated to participate in this qualitative study using focus groups. A topic guide was utilised to standardise data collection. Informants' views were recorded on tape and in field notes. Data were transcribed and analysed using Framework Methodology. Results A total of 99 VDPs participated in the 10 focus groups. Their choice of dentistry as a professional career was motivated by multiple categories of influence: 'academic', 'healthcare', 'lifestyle', the influence of 'family', 'friends', 'careers advice' and 'work experience'. Consideration of the features of the 'professional job' appears to have been key to their choice of dentistry and the 'active rejection of medicine' as an alternative career. Entry into the profession was proving a challenging process for some but not all VDPs. Informants perceived that their vision had been moderated as a result of 'personal student debt', 'national workforce initiatives', 'limitations on clinical practice' and the 'cost of additional training'. Short term goals focused around 'recovery from the past' and 'preparation for the future'. Longterm goals covered the spectrum of opportunities within dentistry. Factors influencing VDPs longterm career plans fell into six main categories: professional, personal, financial, political, social and cultural. Conclusion VDPs chose dentistry because they perceived that it provides a financially lucrative, contained career in healthcare, with professional status, job security and the opportunity to work flexibly. They perceive that their vision is challenged by changes affecting education and the healthcare system. Longterm professional expectations were closely linked with their personal lives and support a vision of a favourable work/life balance.

The identification of a potent series of IKK-β selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-α release mouse model are described.

BMS-505130 is a potent and selective serotonin transport inhibitor; K(i) for binding to the serotonin transporter = 0.18 nM (K(i) values for binding to the norepinephrine and dopamine transporters = 4.6 and 2.1 microM, respectively). In platelet serotonin uptake studies BMS-505130 (5 mg/kg, p.o.) produced a robust inhibition of serotonin uptake. In microdialysis studies oral dosing with BMS-505130 produced a dose-dependent increase in cortical serotonin levels that reached a maximal effect of 200% above baseline at a dose of 1 mg/kg, p.o.; the peak serotonin response was transient in nature. Following oral administration, peak plasma concentrations of BMS-505130 reached Tmax at 1.6 +/- 0.7 h and then declined to concentrations

Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).

The signal-inducible phosphorylation of serines 32 and 36 of I kappa B alpha is critical in regulating the subsequent ubiquitination and proteolysis of I kappa B alpha, which then releases NF-kappa B to promote gene transcription. The multisubunit I kappa B kinase responsible for this phosphorylation contains two catalytic subunits, termed I kappa B kinase (IKK)-1 and IKK-2. BMS-345541 (4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) was identified as a selective inhibitor of the catalytic subunits of IKK (IKK-2 IC(50) = 0.3 microm, IKK-1 IC(50) = 4 microm). The compound failed to inhibit a panel of 15 other kinases and selectively inhibited the stimulated phosphorylation of I kappa B alpha in cells (IC(50) = 4 microm) while failing to affect c-Jun and STAT3 phosphorylation, as well as mitogen-activated protein kinase-activated protein kinase 2 activation in cells. Consistent with the role of IKK/NF-kappa B in the regulation of cytokine transcription, BMS-345541 inhibited lipopolysaccharide-stimulated tumor necrosis factor alpha, interleukin-1 beta, interleukin-8, and interleukin-6 in THP-1 cells with IC(50) values in the 1- to 5-microm range. Although a Dixon plot of the inhibition of IKK-2 by BMS-345541 showed a non-linear relationship indicating non-Michaelis-Menten kinetic binding, the use of multiple inhibition analyses indicated that BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26-42 of I kappa B alpha with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. The opposite results were obtained when studying the binding to IKK-1. A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. BMS-345541 was also shown to have excellent pharmacokinetics in mice, and peroral administration showed the compound to dose-dependently inhibit the production of serum tumor necrosis factor alpha following intraperitoneal challenge with lipopolysaccharide. Thus, the compound is effective against NF-kappa B activation in mice and represents an important tool for investigating the role of IKK in disease models.

The quality ofAtriplex hortensis L. (Mountain Spinach) as a leafy vegetable, forage crop, and plant for production of leaf protein/nutrient concentrate was investigated. The plant can substitute or supplementSpinacia oleracea L. as a leafy vegetable, due to similar chemical composition and a higher leaf yield. The whole plant, as a meal, is similar toMedicago sativa L. in chemical composition. It could be suitable for cultivation in dry areas. By wet-fractionation of the plant a leaf protein concentrate can be obtained. The concentrate is well composed, and should lack anti-nutritive substances present in the whole plant.