The IMS Library: from IN-Stock to Virtual.

A chemical library is a key element in the early stages of pharmaceutical research. Its design encompasses various factors, such as diversity, size, ease of synthesis, aimed at increasing the likelihood of success in drug discovery. This article explores the collaborative efforts of computational and synthetic chemists in tailoring chemical libraries for cost-effective and resource-efficient use, particularly in the context of academic research projects.

Acute, chronic and conditioned effects of intranasal oxytocin in the mu-opioid receptor knockout mouse model of autism: Social context matters.

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results.

A Selective Neutraligand for CXCL12/SDF-1α With Beneficial Regulatory Functions in MRL/Lpr Lupus Prone Mice.

Dysregulation of CXCL12/SDF-1-CXCR4/CD184 signaling is associated with inflammatory diseases and notably with systemic lupus erythematosus. Issued from the lead molecule chalcone-4, the first neutraligand of the CXCL12 chemokine, LIT-927 was recently described as a potent analogue with improved solubility and stability. We aimed to investigate the capacity of LIT-927 to correct immune alterations in lupus-prone MRL/lpr mice and to explore the mechanism of action implemented by this small molecule in this model.

Nile Red-Based GPCR Ligands as Ultrasensitive Probes of the Local Lipid Microenvironment of the Receptor.

The local lipid microenvironment of transmembrane receptors is an essential factor in G protein coupled receptor (GPCR) signaling. However, tools are currently missing for studying endogenously expressed GPCRs in primary cells and tissues. Here, we introduce fluorescent environment-sensitive GPCR ligands for probing the microenvironment of the receptor in living cells using fluorescence microscopy under no-wash conditions.

Neutralization of CXCL12 attenuates established pulmonary hypertension in rats.

Aims: The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models.

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism.

Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD.

Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia.

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor.

Structure-activity relationship studies toward the discovery of selective apelin receptor agonists.

Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial.

Homodimerization of the death-associated protein kinase catalytic domain: development of a new small molecule fluorescent reporter.

Background: Death-Associated Protein Kinase (DAPK) is a member of the Ca2+/calmodulin regulated serine/threonine protein kinases. Its biological function has been associated with induced cell death, and in vivo use of selective small molecule inhibitors of DAPK catalytic activity has demonstrated that it is a potential therapeutic target for treatment of brain injuries and neurodegenerative diseases.

Methodology/principal Findings: In the in vitro study presented here, we describe the homodimerization of DAPK catalytic domain and the crucial role played by its basic loop structure that is part of the molecular fingerprint of death protein kinases.

On the enantioselective olefin epoxidation by doubly bridged biphenyl azepine derivatives--mixed tropos/atropos chiral biaryls.

Diastereomeric doubly bridged biphenyl azepines, atropos at 20 degrees C and tropos at 80 degrees C, are precursors to effective iminium organocatalysts that are employed in the enantioselective epoxidation of prochiral olefins (up to 85% ee).

Biphasic enantioselective olefin epoxidation using Tropos dibenzoazepinium catalysts.

Several novel chiral iminium TRISPHAT [tris(tetrachlorobenzenediolato)phosphate(V)] salts combining a diphenylazepinium core, chiral exocyclic appendages, and lipophilic counterions have been prepared and tested in biphasic enantioselective olefin epoxidation conditions. Interestingly, the iminium salts derived from commercially available (S)- or (R)-1,2,2-trimethylpropylamine can display efficiency similar to those made from L-acetonamine. Variable-temperature NMR spectroscopy (VT-NMR) and circular dichroism (CD) experiments were performed in search of a correlation between good enantioselectivity in the products and high diastereomeric control of the biphenyl axial chirality of the catalysts.