Incidence Rates and Predictors of Recurrent Long-Term Mental Sickness Absence Due to Common Mental Disorders.

Purpose: Several predictors have been identified for mental sickness absence, but those for recurrences are not well-understood. This study assesses recurrence rates for long-term mental sickness absence (LTMSA) within subgroups of common mental disorders (CMDs) and identifies predictors of recurrent LTMSA.

Methods: This historical prospective cohort study used routinely collected data from 16,310 employees obtained from a nationally operating Dutch occupational health service (ArboNed).

Evaluation of Synthetic Cytochrome P-Mimetic Metalloporphyrins To Facilitate "Biomimetic" Biotransformation of a Series of mGlu Allosteric Ligands.

Allosteric ligands within a given chemotype can have the propensity to display a wide range of pharmacology, as well as unexpected changes in GPCR subtype selectivity, typically mediated by single-atom modifications to the ligand. Due to the unexpected nature of these "molecular switches", chemotypes with this property are typically abandoned in lead optimization. Recently, we have found that in vivo oxidative metabolism by CYPs can also engender molecular switches within allosteric ligands, changing the mode of pharmacology and leading to unwanted toxicity.

Evaluation of 1,2,3-Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX-770 and VX-809.

The 1,2,3-triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX-809 and VX-770, prominent amide-containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX-809, displayed markedly reduced efficacy in F508del-CFTR correction in cellular TECC assays in comparison to VX-809.

Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 or M1) antagonist in vitro and in vivo probe.

This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M(1)). An M(1) functional, cell-based calcium-mobilization assay identified three distinct chemical series with initial selectivity for M(1) versus M(4). An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects.

Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists.

This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a novel series of selective M1 mAChR antagonists for the potential treatment of Parkinson's disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5.