Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

[Self-perceived health status in health workers 3 and 6 months after a SARS-CoV-2 infection (COVID-19).] / Estado de salud autopercibido del personal sanitario 3 y 6 meses después de infección por el virus SARS-CoV-2 (COVID-19).

OBJECTIVE: After the acute period of infection by the SARS-CoV-2 virus (COVID-19), multi-organ signs and symptoms may remain. This study tried to compare the perception of the state of health and the sequelae in Navarra-Osasunbidea health workers after COVID-19, with the previous situation through the Health Survey. METHODS: Through a descriptive cross-sectional study, using a reduced questionnaire from the 2017 National Health Survey sent to health workers from the Navarre-Osasunbidea Health Service COVID-19 cases after 3 and 6 months, from April to July 2021 and compared with 2017. Differences were described through means, percentages and prevalence ratio, with 95% confidence intervals. RESULTS: Of 938 surveys sent, 93 of 3 months (46.3%) and 305 of 6 months (41.4%) were received, 87% of women and 13% of men and 43 years of average age and 64.3% were from nursing and 19.1% from medicine. The percentage that assessed their health status as good or very good was significantly lower at 6 months than health workers and the general population in 2017 (70.2% vs 80.4% and 75.5%), the limitation for the habitual activity (39.8% and 35.1% vs 18.3%), headache 2.7 times more frequent, the days of activity restriction (41.5 and 26.7 vs 7.5) and on bed. Mental health problems, concentration (45.2% and 43.9%), loss of sleep (44.1% and 43.3%) and consumption of tranquilizers and antidepressants (2 and 3 times more) stood out, although not of medical consultations. CONCLUSIONS: Navarre health workers diagnosed with COVID-19 in 2020 and early 2021 refer to the worst assessment of their health status at 3 and 6 months, greater limitation for usual activities, more frequent headaches and mental health problems, compared to the pre-pandemic period.

OBJETIVO: Pasado el período agudo de infección por el virus SARS-CoV-2 (COVID-19), pueden permanecer signos y síntomas multiorgánicos. Este estudio trató de comparar la percepción del estado de salud y las secuelas en los sanitarios navarros pasada la COVID-19, con la situación previa mediante Encuesta de Salud. METODOS: Estudio descriptivo transversal, mediante un cuestionario reducido de la Encuesta Nacional de Salud 2017 remitido a los sanitarios del Servicio Navarro de Salud-Osasunbidea, casos de COVID-19 pasados 3 y 6 meses, de abril a julio de 2021 y se comparó con 2017. Se describieron diferencias mediante medias, porcentajes y razón de prevalencia, con intervalos de confianza al 95%. RESULTADOS: De 938 encuestas enviadas, se recibieron 93 de 3 meses (46,3%) y 305 de 6 meses (41,4%), 87% de mujeres y 13% de hombres y 43 años de media de edad. El 64,3% fueron de enfermería y 19,1% de medicina. El porcentaje que valoró su estado de salud como bueno o muy bueno fue significativamente inferior a los 6 meses que sanitarios y población general en 2017 (70,2 % vs. 80,4% y 75,5%), mayor el de limitación para la actividad habitual (39,8% y 35,1% vs 18,3%), 2,7 veces más frecuente el dolor de cabeza y más los días de restricción de actividad (41,5 y 26,7 vs. 7,5) y en cama. Destacaron los problemas de salud mental, concentración (45,2% y 43,9%), pérdida de sueño (44,1% y 43,3%) y consumo de tranquilizantes y antidepresivos (2 y 3 veces más), aunque no de consultas médicas. CONCLUSIONES: Los sanitarios navarros diagnosticados de COVID-19 en 2020 y principios de 2021 refieren a los 3 y 6 meses peor valoración de su estado de salud, mayor limitación para las actividades habituales, más frecuente dolor de cabeza y problemas de salud mental, respecto a período prepandemia.

Benzenesulfonamide indole inhibitors of cytosolic phospholipase A2alpha: optimization of in vitro potency and rat pharmacokinetics for oral efficacy.

The synthesis and structure-activity relationship of a series of benzenesulfonamide indole inhibitors of cPLA(2)alpha are described. Substitution of the benzenesulfonamide led to analogues with 50-fold improvement in potency versus the unsubstituted benzenesulfonamide lead compound. Rat pharmacokinetics in a minimal formulation was used to prioritize compounds, leading to the discovery of a potent inhibitor of cPLA(2)alpha with oral efficacy in models of rat carrageenan paw edema and Ascaris suum airway challenge in naturally sensitized sheep.

Estado de salud autopercibido del personal sanitario 3 y 6 meses después de infección por el virus SARS-CoV-2 (COVID-19) / Self-perceived health status in health workers 3 and 6 months after a SARS-CoV-2 infection (COVID-19)

Fundamentos: Pasado el período agudo de infección por el virus SARS-CoV-2 (COVID-19), pueden permanecer signos y síntomas multiorgánicos. Este estudio trató de comparar la percepción del estado de salud y las secuelas en los sanitarios navarros pasada la COVID-19, con la situación previa mediante Encuesta de Salud. Métodos: Estudio descriptivo transversal, mediante un cuestionario reducido de la Encuesta Nacional de Salud 2017 remitido a los sanitarios del Servicio Navarro de Salud-Osasunbidea, casos de COVID-19 pasados 3 y 6 meses, de abril a julio de 2021 y se comparó con 2017. Se describieron diferencias mediante medias, porcentajes y razón de prevalencia, con intervalos de confianza al 95%. Resultados: De 938 encuestas enviadas, se recibieron 93 de 3 meses (46,3%) y 305 de 6 meses (41,4%), 87% de mujeres y 13% de hombres y 43 años de media de edad. El 64,3% fueron de enfermería y 19,1% de medicina. El porcentaje que valoró su estado de salud como bueno o muy bueno fue significativamente inferior a los 6 meses que sanitarios y población general en 2017 (70,2 % vs. 80,4% y 75,5%), mayor el de limitación para la actividad habitual (39,8% y 35,1% vs 18,3%), 2,7 veces más frecuente el dolor de cabeza y más los días de restricción de actividad (41,5 y 26,7 vs. 7,5) y en cama. Destacaron los problemas de salud mental, concentración (45,2% y 43,9%), pérdida de sueño (44,1% y 43,3%) y consumo de tranquilizantes y antidepresivos (2 y 3 veces más), aunque no de consultas médicas. Conclusiones: Los sanitarios navarros diagnosticados de COVID-19 en 2020 y principios de 2021 refieren a los 3 y 6 meses peor valoración de su estado de salud, mayor limitación para las actividades habituales, más frecuente dolor de cabeza y problemas de salud mental, respecto a período prepandemia.(AU)

Background: After the acute period of infection by the SARS-CoV-2 virus (COVID-19), multirgan signs and symptoms may remain. This study tried to compare the perception of the state of health and the sequelae in Navarra-Osasunbidea health workers after COVID-19, with the previous situation through the Health Survey. Methods: Through a descriptive cross-sectional stuy, using a reduced questionnaire from the 2017 NationalHealth Survey sent to health workers from the Navarre-Osasunbidea Health Service COVID-19 cases after 3 and 6 months, from April to July 2021 and compared with 2017. Differences were described through means, percentages and prevalence ratio, with 95% confidence intervals. Results: Of 938 surveys sent, 93 of 3 months (46.3%) and 305 of 6 months (41.4%) were received, 87% of women and 13% of men and 43 years of average age and 64.3% were from nursing and 19.1% from medicine. The percentage that assessed their health status as good or very good was significantly lower at 6 months th an health workers and the general population in 2017 (70.2% vs 80.4% and 75.5%), the limitation for the habitual activity (39.8% and 35.1% vs 18.3%), headache 2.7 times more frequent, the days of activity restriction (41.5 and 26.7 vs 7.5) and on bed. Mental health problems, concentration (45.2% and 43.9%), loss of sleep (44.1% and 43.3%) and consumption of tranquilizers and antidepressants (2 and 3 times more) stood out, although not of medical consultations. Conclusions: Navarre health workers diagnosed with COVID-19 in 2020 and early 2021 refer to the worst assessment of their health status at 3 and 6 months, greater limitation for usual activities, more frequent headaches and mental health problems, compared to the prepandemic period.(AU)

Patologías broncopulmonares asociadas a la exposición laboral a Fibras Minerales Artificiales: revisión sistemática / Lung diseases associated with occupational exposure to artificial mineral fibers: systematic review

Introducción: las fibras minerales artificiales (FMA) representan un grupo de fibras manufacturadas utilizadas principalmente para aislamiento térmico y acústico y de forma general en el ámbito de la construcción. Debido a que tienen una estructura similar a la fibra de amianto, se tiende a pensar que también pueden desarrollar patologías pulmonares como el cáncer, resultando de interés estudiar la exposición laboral a estas fibras y sus posibles consecuencias en la salud del trabajador. Método: revisión sistemática de la literatura científica mediante la búsqueda bibliográfica en MEDLINE a través de PUBMED, SCOPUS, EMBASE, WOS, Cochrane Library Plus, IBECS, LILACS y CISDOC. Se han recuperado artículos publicados en los últimos 10 años (2.008 al 2.018). Resultados: se obtuvieron 137 referencias de las que tras aplicar los criterios de inclusión y exclusión se recuperaron 8 artículos. Según el diseño del estudio contamos con 2 estudios de cohortes, 5 casos y controles y 1 transversal. En algunos estudios se encontró una asociación positiva pero no estadísticamente significativa entre la exposición laboral y el desarrollo de patología pulmonar. Conclusiones: aún no se dispone de suficiente evidencia científica que apoye una relación directa entre la exposición laboral a fibras minerales artificiales y sus implicaciones en el desarrollo de patología broncopulmonar, por lo tanto, se hace necesario realizar más estudios a largo plazo que aporten evidencia sobre este tema, en vista de la gran cantidad de trabajadores expuestos a estas fibras (AU)

Introduction: man-made mineral fibers represent a group of manufactured fibers used mainly for thermal and acoustic insulation and generally in the field of construction. Because these fibers have a similar structure to asbes-tos, it is a reason to think thatthey can develop pulmonary pathologies such as cancer, resulting in the interest to study the occupational exposure to these fibers and their possible consequences on the worker’s health.Method: Systematic review of scientific articles through bibliographic search in MEDLINE (PUBMED), SCOPUS, EM-BASE, WOS, Cochrane Library Plus, IBECS, LILACS and CISDOC, published over the last 10 years (2.008 to 2.018).Results: 137 references were retrieved, 8 articles remained after applying the inclusion and exclusion criteria. Ac-cording to this, there are 2 cohort studies, 5 cases and controls and 1 cross-sectional study. In some of these studies, a positive but not statistically significant association was found between occupational exposure to man-made min-eral fibers and the development of pulmonary pathology.Conclusions: there is not enough scientific evidence to support a direct relationship between occupational ex-posure to man-made mineral fibers and its implications in the development of bronchopulmonary pathologies, therefore it is necessary to conduct more long-term studies that provide evidence on this subject, in view of the large number of workers exposed to these fibers (AU)

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.