The multicomponent Passerini reaction as a means of accessing diversity in structure, activity and properties: Soft and hard vanilloid/cannabinoid modulators.

A growing body of evidence points to the existence of a crosstalk between the endovanilloid (EV)- and the endocannabinoid (EC) systems, leading to the concept of a single system based on a shared set of endogenous ligands and regulation mechanisms. The EV/EC system encompasses the ion channel TRPV1, the G protein coupled receptors CB1 and CB2, their endogenous ligands and the enzymes for biosynthesis and inactivation. Disorders in which the EV/EC interaction is involved are inflammation, pain, neurodegenerative diseases and disorders of bones and skin.

Correction to "An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline".

[This corrects the article DOI: 10.1021/acsmedchemlett.2c00166.

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs.

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs.

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.

CIC-39Na reverses the thrombocytopenia that characterizes tubular aggregate myopathy.

Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.

STIM1 and ORAI1 mutations leading to tubular aggregate myopathies are sensitive to the Store-operated Ca-entry modulators CIC-37 and CIC-39.

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps.

The [1,2,4]Triazolo[4,3-a]pyridine as a New Player in the Field of IDO1 Catalytic Holo-Inhibitors.

Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure-based virtual screening made on IDO1 active site.

1,2,4-Oxadiazole-Bearing Pyrazoles as Metabolically Stable Modulators of Store-Operated Calcium Entry.

Store-operated calcium entry (SOCE) is a pivotal mechanism in calcium homeostasis, and, despite still being under investigation, its dysregulation is known to be associated with severe human disorders. SOCE modulators are therefore needed both as chemical probes and as therapeutic agents. While many small molecules have been described so far, their poor properties in terms of drug-likeness have limited their translation into the clinical practice.

Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors.

Store-operated calcium entry (SOCE) is important in the maintenance of calcium homeostasis and alterations in this mechanism are responsible for several pathological conditions, including acute pancreatitis. Since the discovery of SOCE, many inhibitors have been identified and extensively used as chemical probes to better elucidate the role played by this cellular mechanism. Nevertheless, only a few have demonstrated drug-like properties so far.