Discovery of GLPG3667, a Selective ATP Competitive Tyrosine Kinase 2 Inhibitor for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) mediates cytokine signaling through type 1 interferon, interleukin (IL)-12/IL-23, and the IL-10 family. There appears to be an association between TYK2 genetic variants and inflammatory conditions, and clinical evidence suggests that selective inhibition of TYK2 could produce a unique therapeutic profile. Here, we describe the discovery of compound 9 (GLPG3667), a reversible and selective TYK2 adenosine triphosphate competitive inhibitor in development for the treatment of inflammatory and autoimmune diseases. The preclinical pharmacokinetic profile was favorable, and TYK2 selectivity was confirmed in peripheral blood mononuclear cells and whole blood assays. Dermal ear inflammation was reduced in an IL-23-induced in vivo mouse model of psoriasis. GLPG3667 also completed a phase 1b study (NCT04594928) in patients with moderate-to-severe psoriasis where clinical effect was shown within the 4 weeks of treatment and it is now in phase 2 trials for the treatment of dermatomyositis (NCT05695950) and systemic lupus erythematosus (NCT05856448).

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.

The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure-activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

Guamara and Cocuixtle: Source of Proteases for the Transformation of Shrimp By-Products into Hydrolysates with Potential Application.

Since the fruits of Bromelia pinguin and Bromelia karatas are rich in proteases, the aim of this research was to optimize the hydrolysis process of cooked white shrimp by-products due to the effect of these proteases. A robust Taguchi L16' design was used to optimize the hydrolysis process. Similarly, the amino acid profile by GC-MS and antioxidant capacity (ABTS and FRAP) were determined. The optimal conditions for hydrolysis of cooked shrimp by-products were pH 8.0, 30 °C, 0.5 h, 1 g of substrate and 100 µg/mL of B. karatas, pH 7.5, 40 °C, 0.5 h, 0.5 g substrate and 100 µg/mL enzyme extract from B. pinguin and pH 7.0, 37 °C, 1 h, 1.5 g substrate and 100 µg/mL enzyme bromelain. The optimized hydrolyzates of B. karatas B. pinguin and bromelain had 8 essential amino acids in their composition. The evaluation of the antioxidant capacity of the hydrolyzates under optimal conditions showed more than 80% inhibition of in ABTS radical, B. karatas hydrolyzates had better higher ferric ion reduction capacity with 10.09 ± 0.02 mM TE/mL. Finally, the use of proteolytic extracts from B. pinguin and B. karatas to optimize hydrolysis process allowed obtaining hydrolyzates of cooked shrimp by-products with potential antioxidant capacity.

Proper Orthogonal Decomposition Analysis Reveals Cell Migration Directionality During Wound Healing.

A proper orthogonal decomposition (POD) order reduction method was implemented to reduce the full high dimensional dynamical system associated with a wound healing cell migration assay to a low-dimensional approximation that identified the prevailing cell trajectories. The POD analysis generated POD modes that were representative of the prevalent cell trajectories. The shapes of the POD modes depended on the location of the cells with respect to the wound and exposure to disturbed (DF) or undisturbed (UF) fluid flow where the net flow was in the antegrade direction with a retrograde component or fully antegrade, respectively. For DF and UF, the POD modes of the downstream cells identified trajectories that moved upstream against the flow, while upstream POD modes exhibited sideways cell migrations. In the absence of flow, no major shape differences were observed in the POD modes on either side of the wound. The POD modes also served to reconstruct the cell migration of individual cells. With as few as three modes, the predominant cell migration trajectories were reconstructed, while the level of accuracy increased with the inclusion of more POD modes. The POD order reduction method successfully identified the predominant cell migratory trajectories under static and varying pulsatile fluid flow conditions serving as a first step in the development of artificial intelligence models of cell migration in disease and development.

Reactivity of Hydrogen-Related Electron Centers in Powders, Layers, and Electrodes Consisting of Anatase TiO2 Nanocrystal Aggregates.

Anatase TiO2 nanoparticle aggregates were used as model systems for studying at different water activities the reactivity of electron centers at semiconductor surfaces. The investigated surface conditions evolve from a solid/vacuum interface to a solid/bulk electrolyte interface. Hydrogen-related electron centers were generated either chemically-upon sample exposure to atomic hydrogen at the semiconductor/gas interface-or electrochemically-upon bias-induced charge accumulation at the semiconductor/electrolyte interface. Based on their corresponding spectroscopic and electrochemical fingerprints, we investigated the reactivity of hydrogen-related electron centers as a function of the interfacial condition and at different levels of complexity, that is, (i) for dehydrated and (partially) dehydroxylated oxide surfaces, (ii) for oxide surfaces covered by a thin film of interfacial water, and (iii) for oxide surfaces in contact with a 0.1 M HClO4 aqueous solution. Visible (Vis) and infrared (IR) spectroscopy evidence a chemical equilibrium between hydrogen atoms in the gas phase and-following their dissociation-electron/proton centers in the oxide. The excess electrons are either localized forming (Vis-active) Ti3+ centers or delocalized as (IR-active) free conduction band electrons. The addition of molecular oxygen to chemically reduced anatase TiO2 nanoparticle aggregates leads to a quantitative quenching of Ti3+ centers, while a fraction of ∼10% of hydrogen-derived conduction band electrons remains in the oxide pointing to a persistent hydrogen doping of the semiconductor. Neither trapped electrons (i.e., Ti3+ centers) nor conduction band electrons react with water or its adsorption products at the oxide surface. However, the presence of an interfacial water layer does not impede the electron transfer to molecular oxygen. At the semiconductor/electrolyte interface, inactivity of trapped electrons with regard to water reduction and electron transfer to oxygen were evidenced by cyclic voltammetry.

Discovery of Selective, Orally Bioavailable Pyrazolopyridine Inhibitors of Protein Kinase Cθ (PKCθ) That Ameliorate Symptoms of Experimental Autoimmune Encephalomyelitis.

PKCθ plays an important role in T cell biology and is a validated target for a number of disease states. A series of potent and selective PKCθ inhibitors were designed and synthesized starting from a HTS hit compound. Cell activity, while initially a challenge to achieve, was built into the series by transforming the nitrile unit of the scaffold into a primary amine, the latter predicted to form a new hydrogen bond to Asp508 near the entrance of the ATP binding site of PKCθ. Significant improvements in physiochemical parameters were observed on introduction of an oxetane group proximal to a primary amine leading to compound 22, which demonstrated a reduction of symptoms in a mouse model of multiple sclerosis.

Selective protein kinase Cθ (PKCθ) inhibitors for the treatment of autoimmune diseases.

Protein kinase Cθ (PKCθ) is a member of a large family of serine/threonine kinases that are involved in diverse cellular functions. PKCθ has roles in T-cell activation and survival, where the dependency of T-cell responses on this enzyme appears to be dictated by both the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that although anti-viral responses are PKCθ-independent, T-cell responses associated with autoimmune diseases are PKCθ-dependent. PKCθ-deficient mice are either resistant to or show markedly reduced symptoms in models of MS (multiple sclerosis), IBD (inflammatory bowel disease), arthritis and asthma. Thus potent and selective inhibition of PKCθ has the potential to block T-cell-mediated autoimmunity without compromising anti-viral responses. The present review describes the design and optimization of potent and selective PKCθ inhibitors and their efficacy in both in vitro and in vivo studies. First, our compounds confirm the critical role for PKCθ in T-cell activation and proliferation and secondly they help to demonstrate that murine and human memory T-cell function continues to be dependent on this enzyme. In addition, these inhibitors demonstrate impressive efficacy in treating established autoimmune disease in murine models of IBD and MS.

Strategies for the modulation of phase II metabolism in a series of PKCε inhibitors.

Extensive phase II metabolism of an advanced PKCε inhibitor resulted in sub-optimal pharmacokinetics in rat marked by elevated clearance. Synthesis of the O-glucuronide metabolite as a standard was followed by three distinct strategies to specifically temper phase II metabolic degradation of the parent molecule. In this study, it was determined that the introduction of proximal polarity to the primary alcohol generally curbed O-glucuronidation and improved PK and physical chemical properties while maintaining potency against the target. Utilization of a Jacobsen hydrolytic kinetic resolution to obtain optically enriched final compounds is also discussed.

Subaortic stenosis surgical correction after previous substernum coloesophagoplasty.

Alternate approaches for aortic valve procedures are rare but occasionally used in cardiac surgery because of previous mediastinum radiotherapy or other procedures that preclude median sternotomy. We present one case of right lateral thoracotomy for membrane subaortic stenosis resection in a child with a restrosternal gastric tube.

Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases.

Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses associated with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).

Structure-based optimization of aminopyridines as PKCθ inhibitors.

The identification of a novel series of PKCθ inhibitors and subsequent optimization using docking based on a crystal structure of PKCθ is described. SAR was rapidly generated around an amino pyridine-ketone hit; (6-aminopyridin-2-yl)(2-aminopyridin-3-yl)methanone 2 leading to compound 21 which significantly inhibits production of IL-2 in a mouse SEB-IL2 model.

Uso de la dexmedetomidina (DXM) en implantación de resincronizador cardiaco: ¿es realmente seguro? / The use of dexmedetomidine (DXM) for implanting a cardiac resynchronization device: is it really safe?

La dexmedetomidina (DXM) es un agonista selectivo de los receptores alfa 2 preganglionares, que actúa tanto en el sistema nervioso central como en el periférico. Desde su incursión en la práctica médica, ha sido utilizada satisfactoriamente en un amplio espectro de procedimientos anestésicos, que van desde sedación hasta intervenciones bajo anestesia general. Dentro de sus principales ventajas se encuentran la estabilidad hemodinámica y la mínima depresión respiratoria. Este artículo describe una terapia de resincronización cardiaca exitosa a través de la implantación deun marcapasos biventricular en un paciente hemodinámicamenteinestable, bajo sedación con DXM y midazolam a bajas dosis.

Dexmedetomidine (DXM) is a selective 2-adrenoreceptor agonist acting over both the central and peripheral nervous system. Since it became available for medical application, DXM has been satisfactorily used for a broad spectrum of anesthetic procedures, ranging from sedation to interventions under general anesthesia. Its key advantages include its hemodynamic stability and minimal respiratory depression. This articleprovides a description of a successful cardiac resynchronization therapy implanting a biventricular pacemaker in a hemodynamically unstable patient under DXM and low-dose midazolamsedation.

Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.

Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

Bloqueo de nervio periférico bajo visión ecográfica en un paciente con cardiodesfibrilador implantable / Peripheral nerve blockade under ecographic vision, in patient with implantable cardiodesfibrilator

Los cardiodesfibriladores implantables (CDI), al igual que los marcapasos intracamerales, son dispositivos de alta complejidad que han revolucionado el manejo de pacientes con alteraciones de la conducción cardiaca. Por sus características intrínsecas, sin embargo, están sometidos a una gran cantidad de interferencia electromagnética. Dentro del entorno quirúrgico, múltiples equipos de monitoria o intervencionismo pueden desencadenar mal funcionamiento de un CDI poniendo en riesgo al paciente de presentar complicaciones hemodinámicas, algunas de ellas letales lo cual hace obligatorio un adecuado conocimiento del funcionamiento de este y de cómo se puede prevenir la aparición de eventos no deseados.

Synthesis and biological evaluation of 2-phenylpyran-4-ones: a new class of orally active cyclooxygenase-2 inhibitors.

A series of 2-phenylpyran-4-ones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.