In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures

The market of new psychoactive substances (NPS) is characterized by a high turnover and thus provides several challenges for analytical toxicology. The analysis of urine samples often requires detailed knowledge about metabolism given that parent compounds either may be present only in small amounts or may not even be excreted. Hence, knowledge of the metabolism of NPS is a prerequisite for the development of reliable analytical methods. The main aim of this work was to elucidate for the first time the pooled human liver S9 fraction metabolism of the nine d-lysergic acid diethylamide (LSD) derivatives 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), N6-ethyl-nor-LSD (ETH-LAD), 1-propionyl-N6-ethyl-nor-LSD (1P-ETH-LAD), N6-allyl-nor-LSD (AL-LAD), N-ethyl-N-cyclopropyl lysergamide (ECPLA), (2′S,4′S)-lysergic acid 2,4-dimethylazetidide (LSZ), and lysergic acid morpholide (LSM-775) by means of liquid chromatography coupled to high-resolution tandem mass spectrometry. Identification of the monooxygenase enzymes involved in the initial metabolic steps was performed using recombinant human enzymes and their contribution confirmed by inhibition experiments. Overall, N-dealkylation and hydroxylation, as well as combinations of these steps predominantly catalyzed by CYP1A2 and CYP3A4, were found. For ALD-52, 1P-LSD, and 1B-LSD, deacylation to LSD was observed. The obtained mass spectral data of all metabolites are essential for reliable analytical detection particularly in urinalysis and for differentiation of the LSD-like compounds as biotransformations also led to structurally identical metabolites. However, in urine of rats after the administration of expected recreational doses and using standard urine screening approaches, parent drugs or metabolites could not be detected

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase

ABSTRACT: The cytosolic metalloenzyme Leukotriene A4 Hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory lipid mediator Leukotriene B4 (LTB4). Genetic deletion as well as pharmacological inhibi-tion of LTA4H in preclinical models have validated this enzyme as an attractive drug target in chronic inflammatory dis-eases. Despite several attempts by different pharmaceutical companies, no LTA4H inhibitor has yet reached the market. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A fo-cused DSF screen for binders of LTA4H afforded fragments 1 and 2 that could be co-crystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006/(S)-22, a picomolar LTA4H inhibitor with exquisite whole blood potency (IC90 = 143 nM) and long-lasting in vivo pharmacodynamic effects. Due to its high selectivity and its ability to suppress LTB4 generation entirely in vivo at low exposures, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently being studied in phase II clinical trials in inflammatory acne, hidradenitis sup-purativa, ulcerative colitis and NASH