[Endoscopic retrieval of migrated gastric band]. / Extracción endoscópica de banda gástrica migrada.

This is a case report of a 47-year-old woman, carrier of an adjustable gastric band since 2018, that developed abdominal pain due to partial migration into the stomach. which was successfully removed endoscopically using Sohendra's lithotriptor.

The surfactant Dioctyl Sodium Sulfosuccinate (DOSS) exposure causes adverse effects in embryos and adults of zebrafish (Danio rerio).

Dioctyl Sodium Sulfosuccinate (DOSS, CAS 577-11-7) is a chemical emulsifying surfactant that is widely used in the food and the cosmetic industry, and it is also the major component of the crude oil chemical dispersant Corexit™. Despite of its wide use, the studies related to its negative effect have been evaluated mainly in marine environments showing that DOSS is highly bioactive, extremely low volatile, and potential to persist in the environment longer than other dispersant components. Up to date, there is no available information of DOSS concentration in freshwater environments, little is known about its downstream fate after excretion and its effect on freshwater organisms. The objective of this study was to evaluate the effect of DOSS at different concentrations in embryos and adults of zebrafish Danio rerio in an acute-static bioassays of 96 h. The median lethal concentration in embryos was 33.3 mg/L. Malformations started to be observed at 10 mg/L. In adults, the gene expression analysis in gill tissues showed a deregulation in genes associated with the antioxidant system and the nucleotide excision repair mechanism. Additionally, Micronuclei (DNA damage) in erythrocytes, and fat degeneration in liver, hypertrophy and hyperplasia in gills, and hyaline drops in kidney tissues were also observed. In conclusion, the concentrations of DOSS evaluated here would be of health relevance to fish based on morphological alterations in embryos and changes in the gene expression profile, DNA damage and tissue impairment in adults.

Integrative description of changes occurring on zebrafish embryos exposed to water-soluble crude oil components and its mixture with a chemical surfactant.

The effects of crude oil spills are an ongoing problem for wildlife and human health in both marine and freshwater aquatic environments. Bioassays of model organisms are a convenient way to assess the potential risks of the substances involved in oil spills. Zebrafish embryos (ZFE) are a useful to reach a fast and detailed description of the toxicity of the pollutants, including both the components of the crude oil itself and substances that are commonly used for crude oil spill mitigation (e.g. surfactants). Here, we evaluated the survival rate, as well as histological, morphological, and proteomic changes in ZFE exposed to Water Accumulated Fraction (WAF) of light crude oil and in mixture with Dioctyl Sulfosuccinate Sodium (DOSS, e.g. CEWAF: Chemically Enhanced WAF), a surfactant that is frequently used in chemical dispersant formulations. Furthermore, we compared the hydrocarbon concentration of WAF and CEWAF of the sublethal dilution. In histological, morphological, and gene expression variables, the ZFE exposed to WAF showed less changes than those exposed to CEWAF. Proteomic changes were more dramatic in ZFE exposed to WAF, with important alterations in spliceosomal and ribosomal proteins, as well as proteins related to eye and retinal photoreceptor development and heart function. We also found that the concentration of high molecular weight hydrocarbons in water was slighly higher in presence of DOSS, but the low molecular weight hydrocarbons concentration was higher in WAF. These results provide an important starting point for identifying useful crude-oil exposure biomarkers in fish species.

Morphological Alterations in the Early Developmental Stages of Zebrafish (Danio rerio; Hamilton 1822) Induced by Exposure to Polystyrene Microparticles.

Microplastics (MPs) are emerging pollutants of widespread concern in aquatic environments. The aim of this study was to evaluate the negative impact of pristine MPs of polystyrene of 100 µm on embryo and larvae of Danio rerio exposed to three environmentally relevant concentrations of polystyrene (3.84 × 10- 6, 3.84 × 10- 7, and 3.84 × 10- 8 g/mL). The exposure effect was evaluated through the general morphology score, biometrics, and integrated biomarker response version 2 index. No mortality was observed but the anatomical structure of fishes was affected showing pigmentation deficiency and alterations in the head region as the main affected endpoints. The general morphology score and the integrated biomarker response values were highly sensitive to address the effect of the three concentrations of MPs used here. Our results provide solid evidence of the negative impact of 100 µm pristine polystyrene MPs exposure on early stages of zebrafish.

[Intra-gastric balloon associated with acute pancreatitis]. / Pancreatitis aguda asociada a balón intragástrico.

We present a clinical case of a young woman with the habit of sleeping in the prone position. She reports that after intragastric balloon placement, she begins with nocturnal episodes of epigastric abdominal pain. The most recent episode was characterized by sudden and intense abdominal pain, elevation of pancreatic enzymes, and imaging findings compatible with acute pancreatitis. After carrying out a systematic approach, other potential causes were ruled out. After removing the intragastric balloon, immediate cessation of the nocturnal episodes of pain was obtained. The etiology was attributed to the mechanical compression phenomena caused by the balloon on the pancreatic body during rest in the prone position. We note that the habit of resting in the prone position would constitute a potential risk factor for acute pancreatitis after intragastric balloon placement, so this factor should be considered when counselling candidates for this technique.diseases.

Comparative Transcriptomes of the Body Wall of Wild and Farmed Sea Cucumber Isostichopus badionotus.

Overfishing of sea cucumber Isostichopus badionotus from Yucatan has led to a major population decline. They are being captured as an alternative to traditional species despite a paucity of information about their health-promoting properties. The transcriptome of the body wall of wild and farmed I. badionotus has now been studied for the first time by an RNA-Seq approach. The functional profile of wild I. badionotus was comparable with data in the literature for other regularly captured species. In contrast, the metabolism of first generation farmed I. badionotus was impaired. This had multiple possible causes including a sub-optimal growth environment and impaired nutrient utilization. Several key metabolic pathways that are important in effective handling and accretion of nutrients and energy, or clearance of harmful cellular metabolites, were disrupted or dysregulated. For instance, collagen mRNAs were greatly reduced and deposition of collagen proteins impaired. Wild I. badionotus is, therefore, a suitable alternative to other widely used species but, at present, the potential of farmed I. badionotus is unclear. The environmental or nutritional factors responsible for their impaired function in culture remain unknown, but the present data gives useful pointers to the underlying problems associated with their aquaculture.

A Semi-Deterministic Random Walk with Resetting.

We consider a discrete-time random walk (xt) which, at random times, is reset to the starting position and performs a deterministic motion between them. We show that the quantity Prxt+1=n+1|xt=n,n→∞ determines if the system is averse, neutral or inclined towards resetting. It also classifies the stationary distribution. Double barrier probabilities, first passage times and the distribution of the escape time from intervals are determined.

[Single balloon enteroscopy in the management of small bowel pathology. Experience of the Small Bowel Unit - British American Hospital from December 2012 to December 2018]. / Enteroscopia asistida por balón simple en el manejo de la patología del intestino delgado. Experiencia de la Unidad de Intestino Delgado de la Clínica Anglo Americana durante el periodo de diciembre del 2012 a diciembre del 2018.

Objetive: To describe our experience with single balloon enteroscopy in the management of small bowel disease in British American Hospital, Lima - Perú. MATERIAL AND METHODS: Descriptive and prospective study. We include all patients that come to perform a single balloon enteroscopy in small bowel unit of British American Hospital within December 2012 to December 2018. RESULTS: We performed 80 procedures of single balloon enteroscopy, 49 were done by oral approach, 31 by rectal approach. Mean age were 60.78 years-old (20 - 88 years). 48 patients (60%) were male. The mean insertion time for oral approach was 80 minutes (55-141 minutes), and for rectal approach was 110 minutes (55-180 minutes). The main indication for single balloon enteroscopy was obscure gastrointestinal bleeding. 6 enteroscopies were performed in patients with altered surgical anatomy (7.5%). 70 of 80 procedures (87.5%) were performed with gastroenterology-administered sedation, using midazolam, pethidine and propofol, without any respiratory or hemodinamic complication. Diagnostics achieved by single balloon enteroscopy were small bowel angiodysplasias (20%), yeyuno ileal ulcers (17.5%) and small bowel neoplasia (7.5%). Paralytic ileus was the most common complication of single balloon enteroscopy, 2 cases, and both cases were associated after no using carbon dioxide insufflation during procedure. CONCLUSION: Obscure gastrointestinal bleeding was the main indication for single balloon enteroscopy. Diagnostics achieved by single balloon enteroscopy were small bowel angiodysplasias (20%), yeyuno ileal ulcers (17.5%) and small bowel neoplasia (7.5%). Paralytic ileus was the most common complication of single balloon enteroscopy, 2 cases, and both cases were associated after no using carbon dioxide insufflation during procedure.

[Endoscopic submucosal dissection of a transpyloric early gastric cáncer. A case report and literature review]. / Disección submucosa endoscópica de cáncer gástrico tempranotranspilórico. Reporte de caso y revisión de la literatura.

The endoscopic sumucosal disection (ESD) is an advanced endoscopic technique that achieves the curative resection of superficial neoplasms of the gastrointestinal tract, getting block exeresis with margins free of neoplasia avoiding surgery. However, tumors located in the esophagogastric junction, or pylorus, are technically more complex to resect by ESD. When a neoplasm settles in the pylorus, the anatomical characteristics of this region can affect the adequate assessment of the margins and the performance of the procedure. We present the case of a 70-year-old male patient who, in a high digestive endoscopy, showed a flat multilobulated lesion of 18 mm x 10 mm, located mostly in the lower 2 quadrants of the pyloric canal and minimal compromise of the upper-posterior quadrant, it mainly covers the gastric side of the pyloric channel and extends into the duodenum. Therefore, it was decided to perform en bloc resection of the lesion with the endoscopic submucosal dissection technique. The ERBEJET system was used with a knife type Hybrid knife, saline injection with methylene blue diluted 0.04% on the distal margin, submucosal injection being complemented with 0.4% hyaluronic acid. A "capsule" or straight transparent distal plastic device was used to be able to pull the lesion and allow anterograde visualization of the margins of resection, including the intraduodenal portion, allowing adequate submucosal dissection. Histopathology showed a moderately differentiated tubular adenocarcinoma with surgical edges free of injury. Thanks to the DSE strategy used, our patient could benefit from the curative resection of his gastric cancer with preservation of the organ and with perfect functionality. This case, the first described in the country, shows the progress of national therapeutic endoscopy.

Non-lethal detection of DNA from Cichlidogyrus spp. (Monogenea, Ancyrocephalinae) in gill mucus of the Nile tilapia Oreochromis niloticus.

Infection of Nile tilapia Oreochromis niloticus by monogeneans of the genus Cichlidogyrus is harmful. Currently, diagnosis of this infection is based on invasive techniques and the identification of isolated parasites by their morphology. To facilitate diagnosis, we have developed a non-lethal polymerase chain reaction (PCR) test for detection of Cichlidogyrus spp. DNA in the gill mucus of O. niloticus, using 5 pairs of specific primers based on Cichlidogyrus sclerosus 28S rRNA (Cicly 1 to Cicly 5) which generate fragments of approximately 188, 180, 150, 159 and 189 bp, respectively. PCR specificity was tested using genomic DNA extracted individually from 175 isolated Cichlidogyrus spp., 75 Gyrodactylus cichlidarum and 75 endopararasitic Enterogyrus spp., as well as from 75 protozoans Trichodina spp. The Cicly primers were used to detect Cichlidogyrus spp. DNA in mucus from the gills of 23 Nile tilapia confirmed to be infected with the parasite. Negative controls consisted of 45 uninfected Nile tilapia. The limit of sensitivity of the assay was 1.2 ng of purified parasite DNA. The Cicly primers did not amplify DNA from the mucus of non-infected Nile tilapia, G. cichlidarum, Trichodina spp. or Enterogyrus spp. In all cases, the sensitivity and specificity of the test were 100%. The sequences of all the amplified fragments showed a high similarity to that of the 28S rRNA region of C. sclerosus (93 to 100% identical to GenBank Accession No. DQ157660.1). We provide evidence for a safe and non-invasive DNA-based diagnostic method for the presence of Cichlidogyrus in the gill mucus of O. niloticus.

Physiological and immunological characterization of Caribbean spiny lobsters Panulirus argus naturally infected with Panulirus argus Virus 1 (PaV1).

The present study compares 13 physiological and immunological variables between a group of healthy Panulirus argus lobsters and a group of lobsters naturally infected with Panulirus argus Virus 1 (PaV1). Viral infection was determined through histopathology and PCR. Ten of the 13 variables differed significantly between the 2 groups. Using these variables, a principal component analysis yielded 2 separate clusters: one corresponding to the healthy group and the other corresponding to the infected group. In particular, infected lobsters exhibited significantly lower levels of osmotic pressure, total hemocyte counts, plasmatic proteins, and total phenoloxidase (PO) activity in plasma, as well as significantly higher levels of cholesterol and acylglycerides. These features are consistent with metabolic wasting, hyperlipidemia, and presumed immune suppression. Infection with PaV1 appears to increase the susceptibility of lobsters to some other opportunistic pathogens, as 61.1% of infected lobsters presented infestations of ciliate epibionts (Epystilis and Zoothamniun) in the gill chamber compared with 11.5% lobsters in the healthy group. Infected lobsters also showed significantly higher levels of total PO activity in degranulated hemocytes and trypsin inhibitor activity, potentially indicating activation of immune response by the PO system during the systemic infection with PaV1.

Emergency department observation of patients with acute heart failure prior to hospital admission: impact on short-term prognosis. / Observación en urgencias previa a la hospitalización en pacientes con insuficiencia cardiaca aguda: impacto sobre el pronóstico a corto plazo.

OBJECTIVES: To analyze whether short-term outcomes are affected when patients diagnosed with acute heart failure (AHF) spend time in an emergency department observation unit (EDOU) before hospital admission. MATERIAL AND METHODS: Baseline and emergency episode data were collected for patients diagnosed with AHF in the EDs of 15 Spanish hospitals. We analyzed crude and adjusted associations between EDOU stay and 30-day mortality (primary outcome) and in-hospital mortality and a prolonged hospital stay of more than 7 days (secondary outcomes). RESULTS: A total of 6597 patients with a median (interquartile range) age of 83 (76-88 years) were studied. Fifty-five percent were women. All were hospitalized for AHF (50% in internal medicine wards, 23% in cardiology, 11% in geriatrics, and 16 in other specialties. Of these patients, 3241 (49%) had had EDOU stays and 3350 (51%) had been admitted immediately, with no EDOU stay. Having an EDOU stay was associated with female sex, dementia or chronic obstructive pulmonary disease, long-term treatment with certain drugs for heart failure, greater baseline deterioration in function, and a higher degree of decompensation. Patients in the EDOU group were more often admitted to an internal medicine ward and had shorter stays; cardiology, geriatric, and intensive care admissions were less likely to have had an EDOU stay. Overall, 30-day mortality was 12.6% (13.7% in the EDOU group and 11.4% in the no-EDOU group; P = .004). In-hospital mortality was 10.4% overall (EDOU, 11.1% and no-EDOU, 9.6%; P = .044). Prolonged hospitalization occurred in 50.0% (EDOU, 48.7% and no-EDOU, 51.2%; P = .046). After adjusting for between-group differences, the EDOU stay was not associated with 30-day mortality (hazard ratio, 1.14; 95% CI, 0.99-1.31). Odds ratios for associations between EDOU stay and in-hospital mortality and prolonged hospital stay, respectively, were 1.09 (95% CI, 0.92-1.29) and 0.91 (95% CI, 0.82-1.01). CONCLUSION: Although mortality higher in patients hospitalized for AHF who spend time in an EDO, the association seems to be accounted for by their worse baseline situation and the greater seriousness of the decompensation episode, not by time spent in the EDOU.

OBJETIVO: Analizar si la estancia en el área de observación de urgencias (AOU) de pacientes que han sido diagnosticados de insuficiencia cardiaca aguda (ICA) y que deben ingresar está asociada con algún cambio en la evolución a corto plazo. METODO: Se recogieron datos basales y clínicos de pacientes diagnosticados de ICA en el servicio de urgencias de 15 hospitales españoles. Se analizó la asociación cruda y ajustada de la estancia en el AOU previa a la hospitalización con mortalidad a 30 días (objetivo primario) y con mortalidad intrahospitalaria e ingreso prolongado (> 7 días) (objetivos secundarios). RESULTADOS: Se incluyeron 6.597 pacientes (mediana = 83 años, RIC = 76-88; mujeres = 55%) hospitalizados por ICA (50% en medicina interna, 23% en cardiología, 11% en geriatría y 16% en otros servicios); de ellos, 3.241 (49%) permanecieron en observación en urgencias (grupo AOU) y 3.350 (51%) hospitalizaron sin observación previa (grupo no-AOU). La observación en urgencias se asoció con ser mujer, tener demencia o enfermedad pulmonar obstructiva crónica, recibir crónicamente fármacos específicos para insuficiencia cardiaca, mayor deterioro funcional basal y mayor gravedad de la descompensación. El grupo AOU más frecuentemente hospitalizó en medicina interna y corta estancia, y menos frecuentemente en cardiología, geriatría y cuidados intensivos. La mortalidad a 30 días fue del 12,6% (AOU = 13,7%, no-AOU = 11,4%, p = 0,004); la mortalidad intrahospitalaria fue del 10,4% (AOU = 11,1%, no-AOU = 9,6%, p = 0,044) y el ingreso prolongado del 50,0% (AOU = 48,7%, no-AOU = 51,2%, p = 0,046). Tras ajustar por las diferencias entre grupos, la estancia en observación en urgencias no se asoció con mortalidad a 30 días (HR = 1,14, IC 95% = 0,99-1,31), mortalidad intrahospitalaria (OR = 1,09, IC 95% = 0,92-1,29) o estancia prolongada (OR = 0,91, IC 95% = 0,82-1,01). CONCLUSIONES: Aunque los pacientes hospitalizados por ICA que permanecen en observación en urgencias presentan mayor mortalidad, esta asociación parece explicarse por su peor situación de base y la mayor gravedad del episodio de descompensación y no por su paso por el AOU.

A first glimpse into the transcriptomic changes induced by the PaV1 infection in the gut of Caribbean spiny lobsters, Panulirus argus (Latreille, 1804) (Decapoda: Achelata: Palinuridae).

The Caribbean spiny lobster, Panulirus argus (Latreille, 1804) supports important fisheries in the Caribbean region. This species is affected by a deadly virus, Panulirus argus Virus 1 (PaV1), the only known pathogenic virus for this species. As infection progresses, the effects of PaV1 on its host become systemic, with far reaching impacts on the host's physiology, including structural injuries to its gastrointestinal organs, such as the hepatopancreas and the gut. This last one becomes highly compromised in the last stages of infection. Since the gut is a key organ for the physiological stability of lobsters, we compared the transcriptomic changes in the gut of juvenile individuals of Panulirus argus naturally infected with PaV1. In the RNA-Seq analysis, we obtained a total of 485 × 106 raw reads. After cleaning, reads were de novo assembled into 68,842 transcripts and 50,257 unigenes. The length of unigenes ranged from 201 bp to 28,717 bp, with a N50 length of 2079, and a GC content of 40.61%. In the differential gene expression analysis, we identified a total of 3405 non redundant differential transcripts, of which 1920 were up-regulated and 1485 were down-regulated. We found alterations in transcripts encoding for proteins involved in transcriptional regulation, splicing, postraductional regulation, protein signaling, transmembrane transport, cytoskeletal regulation, and proteolysis, among others. This is the first insight into the transcriptomic regulation of PaV1-P. argus interaction. The information generated can help to unravel the molecular mechanisms that may intervene in the gut during PaV1 infection.

Rational design and synthesis of aminopiperazinones as ß-secretase (BACE) inhibitors.

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

Gill and liver transcriptomic responses of Achirus lineatus (Neopterygii: Achiridae) exposed to water-accommodated fraction (WAF) of light crude oil reveal an onset of hypoxia-like condition.

Crude oil is one of the most widespread pollutants released into the marine environment, and native species have provided useful information about the effect of crude oil pollution in marine ecosystems. We consider that the lined sole Achirus lineatus can be a useful monitor of the effect of crude oil in the Gulf of Mexico (GoM) because this flounder species has a wide distribution along the GoM, and its response to oil components is relevant. The objective of this study was to compare the transcriptomic changes in liver and gill of adults lined sole fish (Achirus lineatus) exposed to a sublethal acute concentration of water-accommodated fraction (WAF) of light crude oil for 48 h. RNA-Seq was performed to assess the transcriptional changes in both organs. A total of 1073 differentially expressed genes (DEGs) were detected in gills; 662 (61.69%) were upregulated, and 411 (38.30%) were downregulated whereas in liver, 515 DEGs; 306 (59.42%) were upregulated, and 209 (40.58%) were downregulated. Xenobiotic metabolism and redox metabolism, along with DNA repair mechanisms, were activated. The induction of hypoxia-regulated genes and the generalized regulation of multiple signaling pathways support the hypothesis that WAF exposition causes a hypoxia-like condition.

Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor.

Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu2 Receptor PAMs.

Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR2 PAMs.

Alterations in the Gut Microbiota of Zebrafish (Danio rerio) in Response to Water-Soluble Crude Oil Components and Its Mixture With a Chemical Dispersant.

Crude oil spills have caused substantial impacts to aquatic ecosystems. Chemical dispersants are used to palliate the impact of oil spillages, but their use is polemic due to their additional potential toxic effect when mixed with oil-derived components. In this work, we used a 16S-based metagenomic approach to analyze the changes of the gut microbiota of adult zebrafish (Danio rerio) exposed to the water accommodated fraction (WAF) of a light crude oil (35° API gravity), and the chemically enhanced WAF (CEWAF), prepared with Nokomis 3-F4® dispersant. After 96 h of exposure, WAF induced an increase in the alpha and beta diversity, altering the relative abundance of Vibrio, Flavobacterium, and Novosphingobium. In contrast, CEWAF only caused an increase in the beta diversity, and an enrichment of the genus Pseudomona. Both treatments diminished the abundances of Aeromonas, Cetobacterium, Coxiella, Dinghuibacter, and Paucibacter. Moreover, the co-occurrence network among genera was more complex in WAF than in CEWAF, indicating a greater bacterial interaction in response to WAF. Our results indicate that short-term exposure to WAF and CEWAF can induce a dysbiosis in the gut microbiota of D. rerio, but these changes are specific in each treatment.

Detection of Panulirus argus Virus 1 (PaV1) in exported frozen tails of subadult-adult Caribbean spiny lobsters Panulirus argus.

The Caribbean spiny lobster Panulirus argus is a valuable fishing resource and the trade in frozen lobster tails is an important industry. However, the presence of the pathogenic virus Panulirus argus Virus 1 (PaV1), which causes systemic infection in P. argus and is particularly lethal to juvenile individuals, has not been previously examined in imported/exported lobster products. We used PCR assays to determine the presence of PaV1 in abdominal muscle tissue of 22 frozen P. argus tails exported from Belize to Mexico. Based on their size, the tails belonged to subadult-adult lobsters. Using specific primers targeted for PaV1 resulted in 11 tails showing a specific 499 bp band. The sequence of positive amplified fragments showed a high similarity to PaV1 (95% identity with GenBank accession no. EF206313.1). Although the pathogenicity of PaV1 was not evaluated in the present study, our results provide the first evidence of PaV1 in frozen lobster tails exported in the seafood industry as well as the first molecular evidence of PaV1 in adult lobsters.

Evaluation of a Series of ß-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads.

Despite several years of research, only a handful of ß-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. Herein we present a set of novel heteroaryl-fused piperazine amidine inhibitors designed to lower the basicity of the key, enzyme binding, amidine functionality. This study resulted in the identification of highly potent (IC50 ≤ 10 nM), permeable lead compounds with a reduced propensity to suffer from P-glycoprotein-mediated efflux.