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.

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.