RESUMEN
Background: Dry needling (DN) has emerged as a popular therapeutic intervention for managing musculoskeletal pain. While major adverse events are generally rare, those that have been reported in vulnerable areas such as the spine and thorax can be serious and warrant further investigation regarding safe techniques in and around these areas. Purpose: The purpose of this study was to reproduce the methods employed by Williams et al. but with an inferior-medial multifidus DN technique to determine if a dry needle can penetrate the ligamentum flavum (LF) and breach the spinal canal at the thoracolumbar junction. Study Design: Descriptive Cadaveric study. Methods: The procedure was performed on a cadaver in the prone position. The needle was advanced under ultrasound guidance to determine if a 0.30 x 40 mm dry needle inserted lateral to the spinous process of T12 and directed inferior-medially could penetrate the LF and enter the spinal canal. Results: A 0.30 x 40 mm dry needle inserted 1.9 cm lateral to the spinous process of T12 was able to traverse the space between the vertebral laminae of T12 and L1, penetrate the LF, and enter the spinal canal with an inferior-medial needle angulation of 33-degrees medial and 18-degrees inferior. Conclusion: The results of this study demonstrate the feasibility of a dry needle entering the spinal canal at the thoracolumbar junction using an inferior-medial technique. These findings support the potential role of ultrasound guidance in the training and clinical practice of DN, especially in regions where safety issues have been documented. Level of Evidence: Level IV.
RESUMEN
Development of SAR in a 3-cyano-5-fluoro-N-arylbenzamide series of non-competitive antagonists of mGlu(5) using a functional cell-based assay is described in this Letter. Further characterization of selected potent compounds in in vitro assays designed to measure their metabolic stability and protein binding is also presented. Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples.
Asunto(s)
Benzamidas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Regulación Alostérica , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Microsomas Hepáticos/metabolismo , Unión Proteica , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pK(a) of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Alphabeta production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.
Asunto(s)
Aminas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico/metabolismo , Inhibidores Enzimáticos/farmacología , Catálisis , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Regulación Alostérica , Descubrimiento de Drogas , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/química , Compuestos de Anilina/síntesis química , Oxadiazoles/síntesis química , Compuestos de Anilina/química , Cristalografía por Rayos X , Modelos Moleculares , Oxadiazoles/químicaRESUMEN
There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.
Asunto(s)
Antiparkinsonianos/síntesis química , Isoindoles/síntesis química , Ácidos Picolínicos/síntesis química , Receptores de Glutamato Metabotrópico/fisiología , Administración Oral , Regulación Alostérica , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Células CHO , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Cricetinae , Cricetulus , Haloperidol , Humanos , Técnicas In Vitro , Isoindoles/farmacocinética , Isoindoles/farmacología , Microsomas Hepáticos/metabolismo , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
This Letter describes the design and synthesis of tertiary carbinamine macrocyclic inhibitors of the beta-secretase (BACE-1) enzyme. These macrocyclic inhibitors, some of which incorporate novel P2 substituents, display a 2- to 100-fold increase in potency relative to the previously described acyclic analogs while affording greater stability.
Asunto(s)
Aminas/química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Aminas/síntesis química , Ciclización , Diseño de Fármacos , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Relación Estructura-ActividadRESUMEN
Structural modifications of the aminopyridine P(1)(') group of imidazole acetic acid based TAFIa inhibitors led to the discovery of the aminocyclopentyl analog 28, a 1 nM TAFIa inhibitor with CLT(50) functional activity of 14 nM but without selectivity against CPB. While not as active, aminobutyl derivative 27 provided an improved 6.7-fold selectivity for TAFIa versus CPB.