Endocannabinoid involvement in endometriosis

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Discovery of 5‑Chloro-1-(5-chloro-2-(methylsulfonyl)benzyl)-2-imino-1,2-dihydropyridine-3-carboxamide (TAK-259) as a Novel, Selective, and Orally Active α_1D Adrenoceptor Antagonist with Antiurinary Frequency Effects: Reducing Human Ether-a-go-go-Related Gene (hERG) Liabilities

A novel structural class of iminopyridine derivative <b>1</b> was identified as a potent and selective human α_1D adrenoceptor (α_1D adrenergic receptor; α_1D-AR) antagonist against α_1A- and α_1B-AR through screening of an in-house compound library. From initial structure–activity relationship studies, we found lead compound <b>9m</b> with hERG K⁺ channel liability. To develop analogues with reduced hERG K⁺ channel inhibition, a combination of site-directed mutagenesis and docking studies was employed. Further optimization led to the discovery of (<i>R</i>)-<b>9s</b> and <b>9u</b>, which showed antagonistic activity by a bladder strip test in rats with bladder outlet obstruction, as well as ameliorated cystitis-induced urinary frequency in rats. Ultimately, <b>9u</b> was selected as a clinical candidate. This is the first study to show the utility of iminopyridine derivatives as selective α_1D-AR antagonists and evaluate their effects in vivo

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

Background & Aims: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for hepatic fibrosis. Methods: A time-course study in low-density lipoprotein-receptor knockout. Leiden mice on a high-fat diet was performed to identify the temporal dynamics of key processes contributing to NASH and fibrosis. An integrative systems biology approach was used to elucidate candidate markers linked to the active fibrosis process by combining transcriptomics, dynamic proteomics, and histopathology. The translational value of these findings were confirmed using human NASH data sets. Results: High-fat-diet feeding resulted in obesity, hyperlipidemia, insulin resistance, and NASH with fibrosis in a time-dependent manner. Temporal dynamics of key molecular processes involved in the development of NASH were identified, including lipid metabolism, inflammation, oxidative stress, and fibrosis. A data-integrative approach enabled identification of the active fibrotic process preceding histopathologic detection using a novel molecular fibrosis signature. Human studies were used to identify overlap of genes and processes and to perform a network biology-based prioritization to rank top candidate markers representing the early manifestation of fibrosis. Conclusions: An early predictive molecular signature was identified that marked the active profibrotic process before histopathologic fibrosis becomes manifest. Early detection of the onset of NASH and fibrosis enables identification of novel blood-based biomarkers to stratify patients at risk, development of new therapeutics, and help shorten (pre)clinical experimental time frames

Discovery of Vibegron: A Potent and Selective β₃ Adrenergic Receptor Agonist for the Treatment of Overactive Bladder

The discovery of vibegron, a potent and selective human β₃-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β₃-AR agonist MK-0634 (<b>3</b>) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β₃-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described