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. The results demonstrated that the infusion of three structurally diverse and selective GPBAR1 agonists produced marked reductions in vascular tone and blood pressure in dog, but not in rat, as well as reflex tachycardia and a positive inotropic response, effects that manifested in an enhanced cardiac output. Changes in cardiovascular function were unrelated to modulation of the levothyroxine/thyroxine axis and were nitric oxide independent. A direct effect on vascular tone was confirmed in dog isolated vascular rings, whereby concentration-dependent decreases in tension that were tightly correlated with reductions in vascular tone observed in vivo and were blocked by iberiotoxin. Compound concentrations in which cardiovascular effects occurred, both ex vivo and in vivo, could not be separated from those necessary for modulation of GPBAR1-mediated efficacy, resulting in project termination. These results are the first to clearly demonstrate direct and potent peripheral arterial vasodilation due to GPBAR1 stimulation in vivo through activation of large conductance Ca 21 activated potassium channel K Ca 1.1.

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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. Overlapping plasma concentrations of torcetrapib were achieved in all models tested; values ranged from therapeutic to supratherapeutic. In anesthetized rats, intravenous torcetrapib elicited dose-dependent increases in mean arterial pressure (MAP; 2-18 mm Hg above vehicle during the low- and high-dose infusion), and in anesthetized dogs, torcetrapib increased MAP from 4 to 22 mm Hg. In conscious rats, a single oral dose of torcetrapib increased MAP from 10 to 18 mm Hg in the low-dose and high-dose groups, respectively, whereas in conscious dogs, MAP increased from 3 to 12 mm Hg. SHM-1121X produced marked hypotension in the same models. Pharmacokinetic-pharmacodynamic analysis demonstrated strong correlation across the models tested for both compounds. Results suggest that equivalency across models allows for flexibility to address key issues and enable go/no-go during lead optimization without concern for discordant results. The predictive value of each model was validated with torcetrapib and, when put into practice, led to a decisive no-go for SHM-1121X.

Sphingosine‐1‐Phospate (S1P) and S1P receptor agonists elicit mechanism‐based effects on cardiovascular function in vivo. Indeed, FTY‐720 (subtype non‐selective S1PX agonist) produces mild hypertension in patients (2–3 mmHg in a 1‐yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, possibly dependent upon the CV effect in question (e.g. bradycardia/hypertension), and perhaps even species‐dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, the cardiovascular effects of FTY‐720 after acute i.v. infusion in anesthetized rats, and after oral administration for up to 15‐d in telemetry‐instrumented conscious rats, was tested. The more selective S1P1,5 agonist, BAF‐312, was tested in the same models. We demonstrate that acute i.v. infusion (0.1, 0.3, 1.0 mg/kg/20min) of both FTY‐720 and BAF‐312 elicits bradycardia in rat, results suggestive of an S1P1 mediated mechanism. However, while FTY‐720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose‐dependent hypertension after multiple days of oral administration in rat (mean MAP=102, 107, 109 mmHg vs. 97 mmHg in vehicle controls), BAF‐312 (0.3, 3.0, 30.0 mg/kg/d) had no effect on blood pressure suggesting that hypertension produced by FTY‐720 is mediated by a non‐S1P1 subtype, likely S1P3. Moreover, hypertension in the presence of FTY‐720 may imply that FTY‐720 affects renal sodium handling in rats. In summary, results in anesthetized and conscious rats administered FTY‐720 or BAF‐312 suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation.