Comparison of electrode position marking procedures on the cranial surface.

INTRODUCTION: The study aimed to compare the conventional method of electrode marking with a new system, EPlacement, to improve accuracy and reduce the time burden on health care professionals. METHODS: Ten health care professionals marked mannequin heads and adult volunteers using both methods. Time, accuracy, and usability of each method were analyzed. Three neurophysiological diagnostic tests were performed on mannequin heads: reversal pattern visual evoked potential (three electrodes required); somatosensory evoked potentials from the upper and lower extremities (five electrodes required); and standard intraoperative neurophysiological monitoring for spine surgery (nine electrodes required). Precision scanning of the mannequins with structured light and a printed hull were used to determine the actual locations of the electrodes of the 10/20 system. RESULTS: The new method based on the EPlacement device represents an improvement on conventional tape measure (TM) marking and may be considered within the group of advanced methods such as navigation systems since it leads to improvements of 34% (1.7 mm) for electrode positions in the Nasion-Inion and Left tragus-Right tragus lines and 77% (12.5 mm) for electrode positions using the approximate method. It reduces the time spent per test by an average of 1 min compared to the TM method. Health care staff survey results show a positive feedback regarding usability of the new method. CONCLUSIONS: The study showed that the EPlacement device improves accuracy, reduces time, and is easy to use compared to the conventional method of electrode marking. The EPlacement method can facilitate the complex task of electrode marking and ultimately contribute to improved patient outcomes. It has the potential to be widely accepted and implemented in clinical practice.

Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH).

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Discovery, optimization, and biological evaluation of 5-(2-(trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists.

A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 µM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 µM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain.

Discovery of inhibitors of the channel-activating protease prostasin (CAP1/PRSS8) utilizing structure-based design.

Structure-based design was utilized to guide the early stage optimization of a substrate-like inhibitor to afford potent peptidomimetic inhibitors of the channel-activating protease prostasin. The first X-ray crystal structures of prostasin with small molecule inhibitors bound to the active site are also reported.

Solid-phase synthesis of 1,2,5-trisubstituted 4-imidazolidinones.

An efficient method for the preparation of 1,2,5-trisubstituted 4-imidazolidinones is presented. The synthetic approach is based on the formation of an N-[1-(benzotriazol-1-yl)alkyl] moiety on the amino group of a MBHA resin-bound amino acid. The nucleophilic substitution of the benzotriazole group with an amidic nitrogen results in the formation of a five-membered imidazolidinone ring. The reaction is nonstereospecific and produces diastereomers in ratios that vary depending on the substituents on the ring. A variety of N-alpha-alkylated amino acids were cyclized with aromatic, aliphatic, and heterocyclic aldehydes to determine optimal reaction conditions and to select building blocks for the future preparation of a large, diverse range of individual trisubstituted imidazolidinones as well as a mixture-based combinatorial library.