Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Yasuhiko Igawa 0 Martin C. Michel 0 0 Y. Igawa Department of Continence Medicine, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan 1 ) Department of Pharmacology, Johannes Gutenberg University , Obere Zahlbacher Str. 67, 55101 Mainz, Germany 3-Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for 3- vs. 1- and 2-adrenoceptors in studies with cloned receptor subtypes. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular 3-adrenoceptors. While limited effects on other organ systems are expected for 3-adrenoceptor agonists, this requires further investigation. - The overactive bladder syndrome (OAB) is a prevalent condition among adults and occurs with increasing prevalence with advancing age. Currently, no cure is available for this condition, and present symptomatic treatment is based largely on conservative treatment and the use of muscarinic receptor antagonists. However, many patients experience insufficient therapeutic benefit and/or unpleasant side effects including dry mouth and constipation from muscarinic antagonists. Hence, few patients remain on treatment for longer than a few months. In the search for potential alternative OAB treatments, 3-adrenoceptor agonists have emerged as a promising new drug class. The potential of 3-adrenoceptor agonists in OAB treatment is based on findings that the human bladder expresses 3-adrenoceptors and that this is apparently the predominant if not exclusive -adrenoceptor subtype mediating human detrusor relaxation; however, other subtypes may contribute to detrusor relaxation in other species such as rats (Michel and Vrydag 2006). Accordingly, 3-adrenoceptor agonists have proven effective in a wide variety of animal models of OAB (Michel et al. 2011). Against this background, several selective 3-adrenoceptor agonists have undergone clinical proof-of-concept studies including mirabegron (also known as YM 178), ritobegron (also known as KUC-7483 and as KUC-7322 for its active metabolite, which has primarily been used in the in vitro studies), and solabegron (also known as GW427353) (Fig. 1). Mirabegron has recently obtained regulatory approval in several countries. Therefore, we will shortly review the pharmacological profile of these three agonists and discuss needs for future pharmacological studies in this area. Biochemical and cellular studies To characterize the molecular interaction of the 3-adrenoceptor agonists with their receptor, competition radioligand binding and cyclic AMP accumulation studies have been performed, primarily in cell lines transiently or stably H OH H Fig. 1 Chemical structures of mirabegron, ritobegron (shown as active metabolite KUC-7322), and solabegron transfected with the corresponding receptor. In Chinese hamster ovary (CHO) cells stably transfected with rat 3adrenoceptors, mirabegron stimulated cyclic AMP accumulation with an EC50 of 19 nM and an efficacy of 1.0 relative to that of isoprenaline; for 1-adrenoceptors, an EC50 of 610 nM and an intrinsic efficacy of 0.6 was reported, whereas for 2-adrenoceptors efficacy was <0.1 and potency could not be quantified (Hatanaka et al. 2013b). In CHO cells transfected with cynomolgus monkey 3-adrenoceptors, mirabegron stimulated cAMP accumulation with an EC50 of 32 nM and an efficacy relative to isoprenaline of 0.8; the efficacy relative to isoprenaline at 1- and 2-adrenoceptors was only 0.2 and 0.1, respectively (Someya et al. 2010). Two studies on CHO cells transfected with human adrenoceptor subtypes were reported with rather similar results. Thus, mirabegron stimulated cyclic AMP accumulation via 3-adrenoceptors with EC50 values of 22 nM (Takasu et al. 2007) and 1.5 nM (Hatanaka et al. 2013b), its efficacy relative to isoprenaline was 0.8 in both studies; in contrast, efficacy at human 1- and 2-adrenoceptors was only 0.10.2 in both studies, which did not allow quantification of potency. In human embryonic kidney (HEK) cells stably transfected with human 3-adrenoceptors at a density of 121-fmol/mg protein, mirabegron and isoprenaline exhibited apparent affinities of 55 nM and 34 M, respectively, in competition radioligand binding studies, and these affinities were not substantially altered in HEK cells transfected with several naturally occurring gene variants of the receptor (Vrydag et al. 2009). In cyclic AMP accumulation experiments in these HEK cells, mirabegron and isoprenaline exhibited EC50 values of 0.93 and 11.2 nM, respectively, and the efficacy of mirabegron relative to isoprenaline was 0.85, which is in good agreement with the findings in CHO cells (Hatanaka et al. 2013b; Takasu et al. 2007). The potency and efficacy of mirabegron also was not affected by genotype in these experiments. A 24-h pretreatment with 10 M isoprenaline caused desensitization of the cyclic AMP response to freshly added isoprenaline or mirabegron, which primarily consisted of a reduced maximum response for both agonists (Vrydag et al. 2009); this desensitization also was independent of genotype. The potency, efficacy, and selectivity of KUC-7322, the active metabolite of ritobegron, have been tested for cyclic AMP accumulation in CHO cells transiently transfected with each of the three human -adrenoceptor subtypes (Maruyama et al. 2012a). These studies revealed EC50 values of 22,000, 2,300, and 73 nM for KUC-7322 at 1-, 2-, and 3-adrenoceptors, respectively, as compared to 0.91, 0.67, and 12 nM, respectively, for isoprenaline. While KUC-7322 was a full agonist relative to isoprenaline at each of the three subtypes, its selectivity 3- vs. 1- or 2adrenoceptors was 301- and 32-fold, respectively. Two series of experiments have been reported from stably transfected CHO cells measuring cyclic AMP accumulation via human -adrenoceptor subtypes as stimulated by solabegron. In the first series, the EC50 of solabegron at human 1-, 2-, and 3-adrenoceptors was 1,259, 3,981, and 3.98 nM, respectively, as compared to 1.0, 0.16, and 3.16 nM, respectively, for isoprenaline, i.e., solabegron was 1,000- and 316-fold selective for 3- vs. 1- or 2-adrenoceptors (Uehling et al. 2006); in these experiments, the efficacy (...truncated)