G protein-coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a K(Ca)1.1 (BK(Ca))-dependent mechanism.

Bile acids (BAs) and BA receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), represent novel targets for the treatment of metabolic and inflammatory disorders. However, BAs elicit myriad effects on cardiovascular function, although this has not been specifically ascribed to GPBAR1. This study was designed to test whether stimulation of GPBAR1 elicits effects on cardiovascular function that are mechanism based that can be identified in acute ex vivo and in vivo cardiovascular models, to delineate whether effects were due to pathways known to be modulated by BAs, and to establish whether a therapeutic window between in vivo cardiovascular liabilities and on-target efficacy could be defined.

Strategic integration of in vivo cardiovascular models during lead optimization: predictive value of 4 models independent of species, route of administration, and influence of anesthesia.

The strategic integration of in vivo cardiovascular models is important during lead optimization to enable a wide therapeutic index for cardiovascular safety. However, under what conditions (eg, species, route of administration, anesthesia) studies should be performed to drive go/no-go is open to interpretation. Two compounds, torcetrapib and a novel steroid hormone mimetic (SHM-1121X), both with off-target cardiovascular liabilities, were profiled in 4 in vivo cardiovascular models.

Functional biomarkers of musculoskeletal syndrome (MSS) for early in vivo screening of selective MMP-13 inhibitors.

Introduction: Long-term administration of non-selective matrix metalloproteinase (MMP) inhibitors, such as marimastat, in humans elicits musculoskeletal syndrome (MSS), a syndrome characterized by joint damage including pain, stiffness, and inflammation. This pathology is a significant obstacle to the clinical development of MMP inhibitors and in pre-clinical models MSS can be verified only after terminal histopathology. Consequently, we devised a longitudinal and functional readout of MSS in conscious rats treated with marimastat that was validated against terminal histological assessment.