Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Total Synthesis of Pentacyclic (-)-Ambiguine P Using Sequential Indole Functionalizations.

The first synthesis of a pentacyclic ambiguine (ambiguine P) is reported. The synthesis takes advantage of sequential alkylations of an indole core to rapidly construct the pentacyclic framework of the natural product. Key to the success of the synthesis was the use of a Nicholas reaction to alkylate at C2, crafting a fused seven-membered ring that is characteristic of the pentacyclic ambiguines, as well as the use of an amide-directed functionalization at C12 to set a requisite quaternary center. A versatile late-stage intermediate was prepared that may be applicable to the synthesis of the other pentacyclic ambiguines.

The difficult conversation: a qualitative evaluation of the 'Eat Well Move More' family weight management service.

OBJECTIVE: The Eat Well Move More (EWMM) family and child weight management service is a 12-week intervention integrating healthy eating and physical activity education and activities for families and children aged 4-16. EWMM service providers identified low uptake 12 months prior to the evaluation. The aims of this study were to describe referral practices and pathways into the service to identify potential reasons for low referral and uptake rates. RESULTS: We conducted interviews and focus groups with general practitioners (GPs) (n = 4), school nurses, and nursing assistants (n = 12). Data were analysed using thematic analysis. School nurses highlighted three main barriers to making a referral: parent engagement, child autonomy, and concerns over the National Child Measurement Programme letter. GPs highlighted that addressing obesity among children is a 'difficult conversation' with several complex issues related to and sustaining that difficulty. In conclusion, referral into weight management services in the community may persistently lag if a larger and more complex tangle of barriers lie at the point of school nurse and GP decision-making. The national prevalence of, and factors associated with this hesitation to discuss weight management issues with parents and children remains largely unknown.

Oxidative cyclization of prodigiosin by an alkylglycerol monooxygenase-like enzyme.

Prodiginines, which are tripyrrole alkaloids displaying a wide array of bioactivities, occur as linear and cyclic congeners. Identification of an unclustered biosynthetic gene led to the discovery of the enzyme responsible for catalyzing the regiospecific C-H activation and cyclization of prodigiosin to cycloprodigiosin in Pseudoalteromonas rubra. This enzyme is related to alkylglycerol monooxygenase and unrelated to RedG, the Rieske oxygenase that produces cyclized prodiginines in Streptomyces, implying convergent evolution.

Diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years.

BACKGROUND: Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009. OBJECTIVES: To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. SEARCH METHODS: We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) -1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self-esteem.Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. AUTHORS' CONCLUSIONS: We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review.

Parent-only interventions for childhood overweight or obesity in children aged 5 to 11 years.

BACKGROUND: Child and adolescent overweight and obesity have increased globally, and are associated with short- and long-term health consequences. OBJECTIVES: To assess the efficacy of diet, physical activity and behavioural interventions delivered to parents only for the treatment of overweight and obesity in children aged 5 to 11 years. SEARCH METHODS: We performed a systematic literature search of databases including the Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS as well trial registers. We checked references of identified trials and systematic reviews. We applied no language restrictions. The date of the last search was March 2015 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions delivered to parents only for treating overweight or obesity in children aged 5 to 11 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for risk of bias and evaluated overall study quality using the GRADE instrument. Where necessary, we contacted authors for additional information. MAIN RESULTS: We included 20 RCTs, including 3057 participants. The number of participants ranged per trial between 15 and 645. Follow-up ranged between 24 weeks and two years. Eighteen trials were parallel RCTs and two were cluster RCTs. Twelve RCTs had two comparisons and eight RCTs had three comparisons. The interventions varied widely; the duration, content, delivery and follow-up of the interventions were heterogeneous. The comparators also differed. This review categorised the comparisons into four groups: parent-only versus parent-child, parent-only versus waiting list controls, parent-only versus minimal contact interventions and parent-only versus other parent-only interventions.Trial quality was generally low with a large proportion of trials rated as high risk of bias on individual risk of bias criteria.In trials comparing a parent-only intervention with a parent-child intervention, the body mass index (BMI) z score change showed a mean difference (MD) at the longest follow-up period (10 to 24 months) of -0.04 (95% confidence interval (CI) -0.15 to 0.08); P = 0.56; 267 participants; 3 trials; low quality evidence. In trials comparing a parent-only intervention with a waiting list control, the BMI z score change in favour of the parent-only intervention at the longest follow-up period (10-12 months) had an MD of -0.10 (95% CI -0.19 to -0.01); P = 0.04; 136 participants; 2 trials; low quality evidence. BMI z score change of parent-only interventions when compared with minimal contact control interventions at the longest follow-up period (9 to 12 months) showed an MD of 0.01 (95% CI -0.07 to 0.09); P = 0.81; 165 participants; 1 trial; low quality evidence. There were few similarities between interventions and comparators across the included trials in the parent-only intervention versus other parent-only interventions and we did not pool these data. Generally, these trials did not show substantial differences between their respective parent-only groups on BMI outcomes.Other outcomes such as behavioural measures, parent-child relationships and health-related quality of life were reported inconsistently. Adverse effects of the interventions were generally not reported, two trials stated that there were no serious adverse effects. No trials reported on all-cause mortality, morbidity or socioeconomic effects.All results need to be interpreted cautiously because of their low quality, the heterogeneous interventions and comparators, and the high rates of non-completion. AUTHORS' CONCLUSIONS: Parent-only interventions may be an effective treatment option for overweight or obese children aged 5 to 11 years when compared with waiting list controls. Parent-only interventions had similar effects compared with parent-child interventions and compared with those with minimal contact controls. However, the evidence is at present limited; some of the trials had a high risk of bias with loss to follow-up being a particular issue and there was a lack of evidence for several important outcomes. The systematic review has identified 10 ongoing trials that have a parent-only arm, which will contribute to future updates. These trials will improve the robustness of the analyses by type of comparator, and may permit subgroup analysis by intervention component and the setting. Trial reports should provide adequate details about the interventions to be replicated by others. There is a need to conduct and report cost-effectiveness analyses in future trials in order to establish whether parent-only interventions are more cost-effective than parent-child interventions.

Synthesis of Cycloprodigiosin Identifies the Natural Isolate as a Scalemic Mixture.

The enantiomers of the natural product cycloprodigiosin were prepared using an expedient five-step synthetic sequence that takes advantage of a Schöllkopf-Barton-Zard (SBZ) pyrrole annulation with a chiral isocyanoacetate and a nitrocyclohexene derivative. Using chiral HPLC and X-ray crystallographic analyses of the synthetically prepared material and natural isolate (isolated from the marine bacterium Pseudoalteromonas rubra), naturally occurring cycloprodigiosin was determined to be a scalemic mixture occurring in an enantiomeric ratio of 83:17 (R)/(S) at C4'.

Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study.

BACKGROUND: Clinical studies have shown that interventional lowering of serum free thyroxine (FT4) may be associated with extended survival in patients with some terminal cancers. The report of success with this approach in glioblastoma multiforme caused involvement of the author (A.H.) in the prospective consultative management of 23 end-stage solid tumor patients in whom hypothyroxinemia was induced to prolong life. PATIENTS AND METHODS: Patients were self-referred or recommended by attending physicians to the author (A.H.) and had advanced cancers of the brain, ovary, lung, pancreas, salivary gland, and breast or had mesothelioma or soft-tissue sarcoma. Hypothyroxinemia was achieved in euthyroid patients by using methimazole, with the addition of 3,3',5-triiodo-L-thyronine (L-T3) to prevent hypothyroidism and suppress endogenous thyrotropin (TSH). In patients with pre-existent primary hypothyroidism, T3 administration was substituted for T4 replacement. Serum FT4 and TSH concentrations were serially monitored to enable adjustments to drug therapy and prevent clinical hypothyroidism. Survival was measured from the date of hypothyroxinemia induction with T3 or methimazole plus T3. Outcomes were compared with the odds of death based on the Surveillance Epidemiology and End Results and American Joint Committee on Cancer databases and literature reports. RESULTS: The survival time of 83% (19 of 23) of patients exceeded the 20% expected 1-year survival for this hypothyroxinemic, end-stage cancer group. The difference between actual and expected survival was significant. CONCLUSION: Although this is an uncontrolled observational experience with frank limitations, compassionate medical induction of hypothyroxinemia should be considered for patients with advanced cancers to whom other avenues of treatment are closed.

Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.

A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.

Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.

Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.

Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.

The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.