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 (3) 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.

Background & AimsThe 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.MethodsA 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.ResultsHigh-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.ConclusionsAn 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.

This study examined pseudoaffective responses elicited by vaginal distention in urethaneanesthetized rats, and tested hypotheses that responses would be increased by endometriosis (ENDO) and vary with the estrous cycle. Three groups were studied: ENDO, shamENDO, and Naïve. ENDO was induced by autotransplantating small pieces of uterine horn (or, for shamENDO, fat) on mesenteric arteries. Ten weeks later, rats in proestrus or metestrus were anesthetized with urethane. Distendable latex balloons were inserted into the vaginal canal. While an increasing series of vaginal distentions was delivered, changes in electromyographic activity of the external oblique musculature (visceromotor response, VMR) and mean arterial pressure (pressor) responses were simultaneously measured. Vaginal distention produced VMR and pressor responses in all groups. These responses were significantly greater in ENDO than in the other groups, and greater in proestrus than metestrus. Although the overall amount of cystic tissue was greater in proestrous than metestrous rats, there was no correlation between these amounts and VMR or pressor responses. Acute spinalization (T8-T9) and bilateral pelvic, but not hypogastric neurectomy attenuated both VMR and pressor responses, supporting the hypothesis that vaginal nociception involves suprathoracic spinal processing of information conveyed by the pelvic nerve. These effects on VMR and pressor responses to vaginal distention parallel behavioral escape responses to the same stimuli reported previously. The findings encourage continued use of VMR and pressor responses for further investigation of mechanisms underlying pain associated with ENDO and its potential treatment.