Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs

Physical activity and depressive symptoms after stillbirth: informing future interventions

Abstract Background In the United States, approximately one in 110 pregnancies end in stillbirth affecting more than 26,000 women annually. Women experiencing stillbirth have a threefold greater risk of developing depressive symptoms compared to women experiencing live birth. Depression contributes negatively to health outcomes for both mothers and babies subsequent to stillbirth. Physical activity may improve depression in these women, however, little is known about acceptable physical activity interventions for women after stillbirth. This is the purpose of this descriptive exploratory study. Methods Eligible women were between ages 19 and 45, and experienced stillbirth within one year of the study. An online survey was used to ask questions related to 1) pregnancy and family information (i.e., time since stillbirth, weight gain during pregnancy, number of other children) 2) physical activity participation, 3) depressive symptomatology, and 4) demographics. Results One hundred seventy-five women participated in the study (M age = 31.26 ± 5.52). Women reported participating in regular physical activity (at least 150 minutes of moderate activity weekly) before (60%) and during (47%) their pregnancy, as well as after their stillbirth (61%). Only 37% were currently meeting physical activity recommendations. Approximately 88% reported depression (i.e., score of >10 on depression scale). When asked how women cope with depression, anxiety, or grief, 38% said physical activity. Of those that reported using physical activity to cope after stillbirth, they did so to help with depression (58%), weight loss (55%), and better overall physical health (52%). To cope with stillbirth, women used walking (67%), followed by jogging (35%), and yoga (23%). Women who participated in physical activity after stillbirth reported significantly lower depressive symptoms (M = 15.10, SD = 5.32) compared to women who did not participate in physical activity (M = 18.06, SD = 5.57; t = -3.45, p = .001). Conclusions Physical activity may serve as a unique opportunity to help women cope with the multiple mental sequelae after stillbirth. This study provides data to inform healthcare providers about the potential role of physical activity in bereavement and recovery for women who have experienced stillbirth. Additional research is necessary in this vulnerable population.http://deepblue.lib.umich.edu/bitstream/2027.42/109526/1/12884_2014_Article_391.pd

A Phase I and Pharmacologic Study of Weekly Gemcitabine in Combination with Infusional 5-fluorodeoxyuridine and Oral Calcium Leucovorin

Purpose: Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2′-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods: Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results: During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n = 6) or diarrhea (n = 1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 μM (24 h), 16.3 μM (2 h), and 31.9 μM (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions: Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses

The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors

Design and development of a macrocyclic series targeting phosphoinositide 3-kinase δ

A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency

The trophodynamics of Southern Ocean Electrona (Myctophidae) in the Scotia Sea

The Scotia Sea is one of the most productive regions of the Southern Ocean, but its surface waters are experiencing a rapid increase in temperature, which may be changing the behaviour and distribution of many myctophids and their prey species. Electrona antarctica and Electrona carlsbergi are two of the most abundant myctophids in the region, but their ecology is poorly understood and their response to ongoing environmental change is difficult to determine. This study investigated spatial and temporal patterns in their abundance, population structure and diets using mid-water trawl nets deployed across the Scotia Sea during spring, summer and autumn. E. antarctica was the most numerically abundant species (0.09–0.21 ind. 1,000 m−3), with greatest concentrations occurring in the sea-ice sectors. E. carlsbergi occurred in more northern regions, comprising densities of 0.02–0.11 ind. 1,000 m−3. There was evidence of seasonal variation in depth distribution, size-related sexual dimorphism and size-specific vertical stratification for both species. Latitudinal trends in sex ratio and female body size were apparent for E. antarctica. Its diet varied between regions, seasons and size classes, but overall, Euphausia superba, Metridia spp. and Themisto gaudichaudii were the dominant prey items. E. carlsbergi appeared not to recruit in the Scotia Sea. Its diet was dominated by copepods, particularly Rhincalanus gigas and Metridia spp., but regional, seasonal and ontogenetic variations were evident. This study contributes to our understanding of how mid-water food webs are structured in the Southern Ocean and their sensitivity to ongoing environmental change