Predicted 25-hydroxyvitamin D over the adult life and the risk of ovarian cancer.

The evidence from previous studies of serum 25-hydroxyvitamin D [25(OH)D] and ovarian cancer risk are not conclusive. However, 25(OH)D was generally only measured in late adulthood, which may not capture the etiologically relevant exposure periods. We investigated predicted 25(OH)D over the adult lifetime in relation to ovarian cancer risk in a population-based case-control study conducted from 2011 to 2016 in Montreal, Canada (490 cases, 896 controls). Predicted 25(OH)D was computed using previously validated regression models. Unconditional multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for average predicted 25(OH)D over the adult life and risk. In addition, the relative importance of different periods of past 25(OH)D exposure was explored using a weighted cumulative exposure (WCE) model. For each 20 nmol/L increase in average predicted 25(OH)D over the adult life, the aOR (95% CI) was 0.73 (0.55-0.96). In WCE analyses, the inverse association was strongest for exposures 5 to 20 years and 35 to 55 years prior to diagnosis, with aORs (95% CIs) of 0.82 (0.69-0.94) and 0.79 (0.66-1.02), respectively, for each 20 nmol/L increase in predicted 25(OH)D. These results support an inverse association between 25(OH)D in adulthood and ovarian cancer risk.

Factors predicting missing instruments in three cancer randomized clinical trials.

PURPOSE: Missing patient-reported outcome (PRO) data can seriously threaten the validity of randomized clinical trials (RCTs). Identifying which factors predict missing instruments may help researchers develop strategies to prevent it from happening. This study examined the association of factors with time to the first missing instrument after randomization in three cooperative group RCTs. METHODS: We performed descriptive analyses and Cox proportional hazards regressions for three RCTs selected from the Canadian Cancer Trials Group: MA17 (breast cancer), PR7 (prostate cancer), and LY12 (non-Hodgkin's lymphoma). The outcome was the time from randomization to the first missing instrument. Variables for 15 factors were used as covariates based on availability and previously-reported putative associations with missing PRO data. RESULTS: Nine percent of 1352 subjects on MA17, 37% of 923 subjects on PR7, and 59% of 477 subjects on LY12 had a missing instrument. Twenty-five percent of subjects on MA17 had first missing instrument within 4.6 years. The median time to first missing instrument was: not observed for MA17, 7.3 years for PR7, 0.12 years for LY12. Cox regression revealed statistically significant independent associations with outcome for only five factors: baseline age (PR7) and level of well-being (LY12), and centre level of activity (LY12), presence of post-graduate residency training program (MA17, PR7), and centre geographic location (PR7, LY12). CONCLUSION: Many factors reported to have association with missing instruments do not seem to predict time to the first missing instrument after randomization in RCTs. Context is important in understanding the few that may.

A systematic review and development of a classification framework for factors associated with missing patient-reported outcome data.

BACKGROUND/AIMS: Missing patient-reported outcome data can lead to biased results, to loss of power to detect between-treatment differences, and to research waste. Awareness of factors may help researchers reduce missing patient-reported outcome data through study design and trial processes. The aim was to construct a Classification Framework of factors associated with missing patient-reported outcome data in the context of comparative studies. The first step in this process was informed by a systematic review. METHODS: Two databases (MEDLINE and CINAHL) were searched from inception to March 2015 for English articles. Inclusion criteria were (a) relevant to patient-reported outcomes, (b) discussed missing data or compliance in prospective medical studies, and (c) examined predictors or causes of missing data, including reasons identified in actual trial datasets and reported on cover sheets. Two reviewers independently screened titles and abstracts. Discrepancies were discussed with the research team prior to finalizing the list of eligible papers. In completing the systematic review, four particular challenges to synthesizing the extracted information were identified. To address these challenges, operational principles were established by consensus to guide the development of the Classification Framework. RESULTS: A total of 6027 records were screened. In all, 100 papers were eligible and included in the review. Of these, 57% focused on cancer, 23% did not specify disease, and 20% reported for patients with a variety of non-cancer conditions. In total, 40% of the papers offered a descriptive analysis of possible factors associated with missing data, but some papers used other methods. In total, 663 excerpts of text (units), each describing a factor associated with missing patient-reported outcome data, were extracted verbatim. Redundant units were identified and sequestered. Similar units were grouped, and an iterative process of consensus among the investigators was used to reduce these units to a list of factors that met the guiding principles. The list was organized on a framework, using an iterative consensus-based process. The resultant Classification Framework is a summary of the factors associated with missing patient-reported outcome data described in the literature. It consists of 5 components (instrument, participant, centre, staff, and study) and 46 categories, each with one or more sub-categories or examples. CONCLUSION: A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data, organized into 5 main component groups. The Classification Framework may assist researchers to improve the design of new randomized clinical trials and to implement procedures to reduce missing patient-reported outcome data. Further research using the Classification Framework to inform quantitative analyses of missing patient-reported outcome data in existing clinical trials and to inform qualitative inquiry of research staff is planned.

Preliminary evidence on the uptake, use and benefits of the CONSORT-PRO extension.

PURPOSE: This study assessed the uptake of the CONsolidated Standards of Reporting Trials (CONSORT)-Patient-Reported Outcomes (PRO) statement; determined if use of CONSORT-PRO was associated with more complete reporting of PRO endpoints in randomised controlled trials (RCTs) and identified the extent to which high-impact journals publishing RCTs with PRO endpoints endorse CONSORT-PRO. METHODS: CONSORT-PRO citations were identified by systematically searching Medline, EMBASE and Google from 2013 (year CONSORT-PRO released) to 17 December 2015. RCTs that cited CONSORT-PRO (cases) were compared to a comparable control sample of RCTs in terms of adherence to CONSORT-PRO using t tests. General linear models assessed the relationship between CONSORT-PRO score and key, pre-specified variables. The 100 highest-impact journals that published RCTs with PRO endpoints (2014-2015) were identified via a systematic Medline search. Instructions for authors were reviewed to determine whether journals endorsed CONSORT-PRO. RESULTS: Total CONSORT-PRO scores ranged from 47 to 100% for cases and 25-96% for controls. Cases had significantly higher total CONSORT-PRO scores compared to controls: t = 2.64, p = 0.01. 'Citing CONSORT-PRO', 'journal endorsing CONSORT-PRO' and 'dedicated PRO paper' were significant predictors of higher CONSORT-PRO adherence score: R 2 = 0.48, p < 0.001. 11/100 top-ranked journals endorsed CONSORT-PRO in their instructions to authors, seven of these journals published RCTs included as cases in this study. CONCLUSION: This study demonstrated improved PRO reporting associated with journal endorsement and author use of the CONSORT-PRO extension. Despite growing awareness, more work is needed to promote appropriate use of CONSORT-PRO to improve completeness of reporting; in particular, stronger journal endorsement of CONSORT-PRO.

Multi-trophic level response to extreme metal contamination from gold mining in a subarctic lake.

Giant Mine, located in the city of Yellowknife (Northwest Territories, Canada), is a dramatic example of subarctic legacy contamination from mining activities, with remediation costs projected to exceed $1 billion. Operational between 1948 and 2004, gold extraction at Giant Mine released large quantities of arsenic and metals from the roasting of arsenopyrite ore. We examined the long-term ecological effects of roaster emissions on Pocket Lake, a small lake at the edge of the Giant Mine lease boundary, using a spectrum of palaeoenvironmental approaches. A dated sedimentary profile tracked striking increases (approx. 1700%) in arsenic concentrations coeval with the initiation of Giant Mine operations. Large increases in mercury, antimony and lead also occurred. Synchronous changes in biological indicator assemblages from multiple aquatic trophic levels, in both benthic and pelagic habitats, indicate dramatic ecological responses to extreme metal(loid) contamination. At the peak of contamination, all Cladocera, a keystone group of primary consumers, as well as all planktonic diatoms, were functionally lost from the sediment record. No biological recovery has been inferred, despite the fact that the bulk of metal(loid) emissions occurred more than 50 years ago, and the cessation of all ore-roasting activities in Yellowknife in 1999.

Lacustrine Arcellinina (Testate Amoebae) as Bioindicators of Arsenic Contamination.

Arcellininids (testate amoebae) were examined from 61 surface sediment samples collected from 59 lakes in the vicinity of former gold mines, notably Giant Mine, near Yellowknife, Northwest Territories, Canada to determine their utility as bioindicators of arsenic (As), which occurs both as a byproduct of gold extraction at mines in the area and ore-bearing outcrops. Cluster analysis (Q-R-mode) and detrended correspondence analysis (DCA) reveal five arcellininid assemblages, three of which are related to varying As concentrations in the sediment samples. Redundancy analysis (RDA) showed that 14 statistically significant environmental parameters explained 57 % of the variation in faunal distribution, while partial RDA indicated that As had the greatest influence on assemblage variance (10.7 %; p < 0.10). Stress-indicating species (primarily centropyxids) characterized the faunas of samples with high As concentrations (median = 121.7 ppm, max > 10000 ppm, min = 16.1 ppm, n = 32), while difflugiid dominated assemblages were prevalent in substrates with relatively low As concentrations (median = 30.2 ppm, max = 905.2 ppm, min = 6.3 ppm, n = 20). Most of the lakes with very high As levels are located downwind (N and W) of the former Giant Mine roaster stack where refractory ore was roasted and substantial quantities of As were released (as As2O3) to the atmosphere in the first decade of mining. This spatial pattern suggests that a significant proportion of the observed As, in at least these lakes, are industrially derived. The results of this study highlight the sensitivity of Arcellinina to As and confirm that the group has considerable potential for assessing the impact of As contamination on lakes.

Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans.

The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 [(R)-3-[(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)amino]methylbenzoic acid]. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.

Watershed hydrology mediates the recovery of an arsenic impacted subarctic landscape.

A holistic understanding of the chemical recovery of lakes from arsenic (As) pollution requires consideration of within-lake biogeochemical cycling of As and processes occurring in the surrounding catchment. This study used a watershed mass balance approach, complemented by experimental sediment incubations, to assess the mobility and transport of As within a subarctic watershed (155 km2) impacted by more than 60 years of atmospheric mining emissions. The period of record spanned a transition from drought to high streamflow between September 2017 and September 2019, which yielded insights into the interacting effects of hydrology and within-lake biogeochemical cycling of As. Internal loading of As from contaminated lake sediments (25-46 kg As year-1) and contributions from terrestrial sources (16-56 kg As yr-1) continue to negatively impact lake water quality (19-144 µg As L-1), but the relative importance of these loads varies seasonally and inter-annually in response to changing hydrological conditions. Wet conditions resulted in greater transport of As from terrestrial reservoirs and upstream areas, shorter lake water retention time, and increased the downstream export of As. During dry periods, the lake was disconnected from the surrounding watershed resulting in limited terrestrial contributions and longer lake water residence time, which delayed recovery due to the greater relative influence of internal loading from contaminated sediments. This study highlights that changing hydroclimatic regimes will alter trajectories of chemical recovery for arsenic impacted lakes through the coupling of within-lake and watershed transport processes.

Measuring prognostic awareness in patients with advanced cancer: a scoping review and interpretive synthesis of the impact of hope.

BACKGROUND: Assessment of prognostic awareness (PA) in patients with advanced cancer is challenging because patient responses often indicate their hopes. The objectives of this scoping review were to summarize studies that measured PA in patients with advanced cancer and to synthesize data about how PA was measured and whether hope was incorporated into the measurement. METHODS: MEDLINE and Embase databases were searched from inception to December 14, 2021. Data regarding the impact of hope on assessment of PA were extracted when studies reported on patients' beliefs about prognosis and patients' beliefs about their doctor's opinion about prognosis. An interpretive synthesis approach was used to analyze the data and to generate a theory regarding the incorporation of hope into the assessment of PA. RESULTS: In total, 52 studies representing 23 766 patients were included. Most were conducted in high-income countries and measured PA based on the goal of treatment (curable vs incurable). Five studies incorporated hope into the assessment of PA and reported that among patients who responded that their treatment goal was a cure, an average of 30% also acknowledged that their doctors were treating them with palliative intent. Interpretive synthesis of the evidence generated a trinary conceptualization of PA patients who are aware and accepting of their prognosis; aware and not accepting; and truly unaware. Each of these groups will benefit from different types of interventions to support their evolving PA. CONCLUSION: The trinary conceptualization of PA may promote understanding of the impact of hope in the assessment of PA and guide future research.

Remobilization of legacy arsenic from sediment in a large subarctic waterbody impacted by gold mining.

Arsenic contamination from mining poses an environmental challenge due to the mobility of this redox-sensitive element. This study evaluated arsenic mobility in sediments of Yellowknife Bay (Canada), a large subarctic water body impacted by gold mining during the 20th century. Short-term measurements of arsenic flux from sediment, arsenic profiling of the water column and sediment porewater, and mass balance modelling were conducted to assess the importance of sediment as an arsenic source. Sediment arsenic fluxes were highly variable throughout Yellowknife Bay and ranged from - 65-1520 µg m-2 day-1. Elevated fluxes measured near the mine site were among the highest published for well-oxygenated lakes. Redox boundaries were typically 2-3 cm below the sediment surface as indicated by porewater profiles of iron, manganese, and arsenic, with arsenic maxima of 65-3220 µg L-1 predominately as arsenite. Sediment arsenic flux was positively related to its solid-phase concentration. Modelling indicated sediment was a principal source of arsenic to the water column. Adsorption and precipitation processes in the oxidizing environment of near-surface sediments did not effectively attenuate arsenic remobilized from contaminated sediments. Internal recycling of legacy arsenic between sediment and surface water will impede a return to background conditions in Yellowknife Bay for decades.

Experimental investigation of short-term warming on arsenic flux from contaminated sediments of two well-oxygenated subarctic lakes.

Legacy arsenic (As) contamination from past mining operations remains an environmental concern in lakes of the Yellowknife area (Northwest Territories, Canada) due to its post-depositional mobility in sediment and potential for continued remobilization to surface waters. Warmer temperatures associated with climate change in this subarctic region may impact As internal loading from lake sediments either by a direct effect on sediment porewater diffusion rate or indirect effects on microbial metabolism and sediment redox conditions. This study assessed the influence of warmer temperatures on As diffusion from contaminated sediment of two lakes with contrasting sediment characteristics using an experimental incubation approach. Sediments from Yellowknife Bay (on Great Slave Lake) contained predominately clay and silt with low organic matter (10%) and high As content (1675 µg/g) while sediments of Lower Martin Lake had high organic matter content (~70%) and approximately half the As (822 µg/g). Duplicate sediment batches from each lake were incubated in a temperature-controlled chamber, and overlying water was kept well-oxygenated while As flux from sediment was measured during four weekly temperature treatments (7°C to 21°C, at ~5°C intervals). During the experiment, As diffused from sediment to overlying water in all cores and temperature treatments, with As fluxes ranging from 48-956 µg/m2/day. Arsenic fluxes were greater from Yellowknife Bay sediments, which had higher solid-phase As concentrations, compared to those of Lower Martin Lake. Short-term warming did not stimulate As flux from duplicate cores of either sediment type, in contrast with reported temperature enhancement in other published studies. We conclude that warmer temperatures were insufficient to strongly enhance sediment As diffusion into overlying oxic waters. These observations are relevant for evaluating climate-warming effects on sediment As mobility in subarctic lakes with little or no thermal stratification and a well-oxygenated water column.

Clinical research associates experience with missing patient reported outcomes data in cancer randomized controlled trials.

BACKGROUND: Missing patient reported outcomes data threaten the validity of PRO-specific findings and conclusions from randomized controlled trials by introducing bias due to data missing not at random. Clinical Research Associates are a largely unexplored source for informing understanding of potential causes of missing PRO data. The purpose of this qualitative research was to describe factors that influence missing PRO data, as revealed through the lived experience of CRAs. METHODS: Maximum variation sampling was used to select CRAs having a range of experiences with missing PRO data from academic or nonacademic centers in different geographic locations of Canada. Semistructured interviews were audio-recorded, transcribed verbatim, and analyzed according to descriptive phenomenology. RESULTS: Eleven CRAs were interviewed. Analysis revealed several factors that influence missing PRO data that were organized within themes. PROs for routine clinical care compete with PROs for RCTs. Both the paper and electronic formats have benefits and drawbacks. Missing PRO data are influenced by characteristics of the instruments and of the patients. Assessment of PROs at progression of disease is particularly difficult. Deficiencies in center research infrastructure can contribute. CRAs develop relationships with patients that may help reduce missing PRO data. It is not always possible to provide sufficient time to complete the instrument. There is a need for field guidance and a motivation among CRAs to contribute their knowledge to address issues. CONCLUSION: These results enhance understanding of factors influencing missing PRO data and have important implications for designing operational solutions to improve data quality on cancer RCTs.

Eutrophication and climatic changes lead to unprecedented cyanobacterial blooms in a Canadian sub-Arctic landscape.

Cyanobacterial blooms have been increasing in frequency and intensity but are often considered an issue restricted to temperate and tropical lakes. Here we report on one of the first occurrences of recurring cyanobacterial (Planktothrix spp.) blooms in a sub-Arctic lake from Yellowknife (Northwest Territories, Canada) and provide a long-term environmental context for the recent blooms using local meteorological data and multi-proxy paleolimnological analyses. Multiple co-occurring regional (gold mining emissions and climatic change) and local (land clearance and urbanization) stressors have impacted Jackfish Lake during the 20th and early-21st centuries, which have led to biological responses across multiple trophic levels. The unprecedented post-2013 cyanobacterial blooms were likely a cumulative response to nutrient enrichment and complex climate-mediated changes to lake thermal properties. A regional analysis of eight lakes around Yellowknife revealed that reduced ice cover duration and longer growing seasons have led to an increase in whole-lake primary production, whilst urban lakes were also fertilized by nutrients from local land-use changes in their catchments. Our findings suggest that anthropogenically nutrient-enriched sub-Arctic lakes, akin to their lower-latitude counterparts, may be vulnerable to cyanobacterial blooms in a warming world.

Mineralogical, geospatial, and statistical methods combined to estimate geochemical background of arsenic in soils for an area impacted by legacy mining pollution.

The estimation of geochemical background is complex in areas impacted by point sources of atmospheric emissions due to unknowns about pollutant dispersion, persistence of pollutants on the landscape, and natural concentrations of elements associated with parent material. This study combined mineralogical analysis with conventional statistical and geospatial methods to separate anthropogenically impacted soils from unimpacted soils in the Yellowknife area, Northwest Territories, Canada, a region that was exposed to 60 years of arsenic (As)-rich atmospheric mining emissions (1938-1999) and that hosts natural enrichments of As. High concentrations of As (up to 4700 mg kg-1) were measured in publicly accessible soils near decommissioned roaster stacks in the region and strong relationships between As and distance from the main emission sources persisted in surface soils and soils at depth in the soil profile more than 60 years after the bulk of mining emissions were released. Mineralogical analysis provided unambiguous evidence regarding the source of As minerals and highlighted that most As in surface soils within 15 km of Yellowknife is hosted as anthropogenic arsenic trioxide (As2O3), produced by roaster stack emissions. Statistical protocols for the estimation of geochemical background were applied to an existing database of till geochemistry (N = 1490) after removing samples from mining impacted areas. Results suggested geochemical background for the region is 0.25-15 mg kg-1 As, comparable to global averages, with upper thresholds elevated in volcanic units (30 mg kg-1 As) that often host sulfide mineralization in greenstone belts in the region.

1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity.

A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.

Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum.

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.

1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.

1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 inhibitors resulting in the advancement of a clinical candidate.

1-(2-(2,2,2-trifluoroethoxy)ethyl-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.

1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.

Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.