mirabegron and solabegron

Mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. Because β3-adrenoceptors are expressed in cardiovascular (CV) tissues, there are concerns that OAB treatment with β3-adrenoceptor agonists may affect the heart and vasculature.. To provide a summary of CV effects of β3-adrenoceptor agonists in clinical studies.. A systematic literature search from inception until November 2014 was performed on studies in PubMed and Medline.. Twenty papers, published between 1994 and 2014, were identified: mirabegron (16), solabegron (2), AK-677 (1), and BRL35135 (1). More detailed CV data from mirabegron studies were available in online regulatory documents filed with the US Food and Drug Administration and the UK National Institute for Health and Care Excellence.. The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, currently first-line therapy for OAB.. In this review we looked at the cardiovascular (CV) effects of β3-adrenoceptor agonists used for the treatment of overactive bladder (OAB). The CV safety of mirabegron (the only clinically approved β3-adrenoceptor agonist) appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, the current first-line therapy for OAB.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Electrocardiography; Heart Rate; Humans; Thiazoles; Urinary Bladder, Overactive

We have reviewed the safety and tolerability of β3-adrenoceptor agonists, specifically mirabegron and solabegron, a newly emerging drug class for the treatment of the overactive bladder syndrome. We discuss them mechanistically in the context of expression and other preclinical data.. Based on a systematic PubMed search, incidence of overall adverse events, hypertension, dry mouth, and constipation are comparable between mirabegron or solabegron and placebo. Hypertension is the most frequently observed adverse event, but has a similar incidence with mirabegron and placebo. Nevertheless, severe uncontrolled hypertension has become a contraindication for use of mirabegron based on observation of severe hypertension in association with mirabegron exposure. The overall incidence of adverse events is also similar between mirabegron and the muscarinic receptor antagonist tolterodine, but the incidence of dry mouth is much lower with mirabegron.. The high β3-adrenoceptor mRNA expression in the human ovaries is not associated with reproductive side effects. Generally, β3-adrenoceptors exhibit a rather restricted expression in human tissues, which may explain the overall good tolerability of agonists acting on this receptor. We propose that expression profiles and functional preclinical studies can be important tools in the prediction of adverse event profiles in first-in-class drugs.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Animals; Benzoates; Biphenyl Compounds; Gene Expression Profiling; Humans; Receptors, Adrenergic, beta-3; Thiazoles; Urinary Bladder, Overactive

Overactive bladder (OAB) is a common syndrome that affects both men and women. First-line therapies for the management of OAB symptoms consist of antimuscarinic agents and behavioral therapy, ideally used in combination. Although effective in improving OAB symptoms, the use of antimuscarinic therapy may be limited by side effects, contraindications, and insufficient response. Current second-line therapies include sacral nerve stimulation and percutaneous tibial nerve stimulation. These therapies have been shown to be useful in treating OAB symptoms, but are more invasive and time-consuming than medical therapy. Onabotulinum toxin A is currently under investigation for idiopathic OAB, as well as the β-3-adreno-renoreceptor agonists mirabegron and solabegron. The role of these agents, with different mechanisms of action, in the pharmacologic management of OAB remains to be determined, although they appear to be promising alternatives and possible adjuncts to current pharmacologic and behavioral therapy. This article discusses second-line and current and future therapies for the management of OAB symptoms.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Behavior Therapy; Benzoates; Biphenyl Compounds; Botulinum Toxins, Type A; Clinical Trials as Topic; Electric Stimulation Therapy; Humans; Muscarinic Antagonists; Neuromuscular Agents; Sacrum; Thiazoles; Tibial Nerve; Urinary Bladder, Overactive

β3-Adrenoceptor (AR) agonists are used to treat patients with an overactive bladder (OAB). Clinical proof-of-concept data have been obtained for the β3-AR agonists vibegron, mirabegron, solabegron, and ritobegron; however, the selectivities of these agents have not been compared directly under the same experimental conditions. Moreover, the bladders of some patients express lower β3-AR densities than those of healthy individuals, and the β3-AR density might be expected to affect agonist activity. This study assessed the β3-AR selectivities of four β3-AR agonists and examined the effects of β-AR density on their pharmacological profiles. Functional cellular assays were performed using Chinese hamster ovary-K1 cells expressing three human β-AR subtypes transfected with different amounts of plasmid DNA (0.1, 0.05, 0.025 μg/well). The half-maximal effective concentration values, intrinsic activities (IAs), and β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were calculated to assess their pharmacological profiles. The β3-AR selectivities of vibegron, mirabegron, solabegron, and ritobegron were >7937-, 517-, 21.3-, and >124-fold higher than for β1-ARs, and >7937-, 496-, >362- and 28.1-fold higher than for β2-ARs, respectively, under the same experimental conditions. The IAs of mirabegron, solabegron, and ritobegron decreased in line with decreasing receptor density, while the IA of vibegron was maintained at the same level as that of the full agonist isoproterenol at various β3-AR densities. Vibegron has high β3-AR selectivity and exhibits full agonist activity, regardless of the β3-AR density. These results suggest that vibegron is a highly effective and safe drug for treating OAB.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Receptors, Adrenergic, beta-3

The relaxant effect of an aryloxypropanolamine β3-adrenoceptor agonist on carbachol pre-contracted human detrusor muscle strips was evaluated and compared with literature results from reference compounds of similar mode of action, including mirabegron. A significant relaxation was observed for rac-4-{2-hydroxy-3-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino]propoxy}-2-(hydroxymethyl)phenol which was similar to that exerted by mirabegron. In order to allow for a thorough discussion of results in comparison to reference compounds, their affinity, selectivity and efficacy as hβ3-AR agonists have been evaluated and discussed thoroughly. A ranking of hβ3-AR agonists by relative efficacy resulted in the closest analogy to the order of relaxation potential, with only the relaxant effect of mirabegron not reflecting its excellent relative efficacy as such.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Aniline Compounds; Benzoates; Biphenyl Compounds; Carbachol; Dose-Response Relationship, Drug; Female; Humans; In Vitro Techniques; Ligands; Male; Muscle Relaxation; Muscle, Smooth; Propanolamines; Receptors, Adrenergic, beta-3; Thiazoles; Urinary Bladder