Safety Considerations When Dry Needling the Multifidi in the Thoracolumbar Region: A Cadaveric Study.

Background: Dry needling the lumbar multifidi is a technique used by physical therapists to effectively treat low back pain. While studies have examined the safety considerations in the upper lumbar spine related to the kidneys and lungs, none have investigated the possibility of entering the spinal canal in this region. Purpose: The purpose of this cadaveric ultrasound-guided dry needling exploration was to determine if a dry needle can penetrate the ligamentum flavum at the T12/L1 interspace and enter the spinal canal using a paramedian approach in a fresh-frozen, lightly fixed cadaver in the prone position. Study Design: 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 50 mm dry needle inserted 1.0 cm lateral to the spinous process of T12 and directed medially at a 22-degree angle could penetrate the ligamentum flavum and enter the spinal canal. Results: As determined via ultrasound, a dry needle can penetrate the ligamentum flavum and enter the spinal canal at the thoracolumbar junction using this technique. Conclusion: This interprofessional collaboration demonstrates that a dry needle can penetrate the ligamentum flavum to enter the spinal canal at T12/L1 using a documented technique for dry needling the multifidus. A thorough understanding of human anatomy along with the incorporation of available technology, such as ultrasound, may decrease the risk of adverse events when dry needling the multifidi at the thoracolumbar junction. Level of Evidence: Level IV.

3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats.

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.

SAR of tertiary carbinamine derived BACE1 inhibitors: role of aspartate ligand amine pKa in enzyme inhibition.

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.

Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype.

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.

Discovery of oxadiazoyl tertiary carbinamine inhibitors of beta-secretase (BACE-1).

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.

Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.

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.

Comparison of topological, shape, and docking methods in virtual screening.

Virtual screening benchmarking studies were carried out on 11 targets to evaluate the performance of three commonly used approaches: 2D ligand similarity (Daylight, TOPOSIM), 3D ligand similarity (SQW, ROCS), and protein structure-based docking (FLOG, FRED, Glide). Active and decoy compound sets were assembled from both the MDDR and the Merck compound databases. Averaged over multiple targets, ligand-based methods outperformed docking algorithms. This was true for 3D ligand-based methods only when chemical typing was included. Using mean enrichment factor as a performance metric, Glide appears to be the best docking method among the three with FRED a close second. Results for all virtual screening methods are database dependent and can vary greatly for particular targets.

Design, synthesis, and SAR of macrocyclic tertiary carbinamine BACE-1 inhibitors.

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.

Imidazole acetic acid TAFIa inhibitors: SAR studies centered around the basic P(1)(') group.

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.