Effects of Ritobegron (KUC-7483), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

Abstract

We evaluated the pharmacological profile of ritobegron [KUC-7483; (Ϫ)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC 50 8.2 Ϯ 2.3 ϫ 10 Ϫ7 M; maximal relaxation 88.7 Ϯ 3.7%). The ␤ 3 -adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK B value 6.56 Ϯ 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC 50 6.5 Ϯ 1.2 ϫ 10 Ϫ5 M). Ritobegron had no effect on tracheal contraction at concentrations from 10 Ϫ9 to 10 Ϫ4 M, and even at the highest concentration tested, 10 Ϫ3 M, the maximal relaxation it induced was only 26.7 Ϯ 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3-and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED 50 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ␤ 3 -AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.

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

“…In enfluraneanesthetized cynomolgus monkeys intraduodenal administration of ritobegron dose-dependently reduced intravesicular pressure without significantly affecting heart rate or mean blood pressure, whereas i.v. administration of isoprenaline after ritobegron increased heart rate and reduced blood pressure (Maruyama et al 2012b).…”

“…KUC-7322 also depressed spontaneous contractions of rat colon with an EC 50 of 4.3 nM, and this was inhibited by SR 58,894A, indicating mediation via a β 3 -adrenoceptor (Yamazaki et al 2002). In the isolated cynomolgus monkey bladder, both KUC-7322 and isoprenaline were less potent than in the rat, but KUC-7322 remained a full agonist (Maruyama et al 2012b). Similar to the rat studies, KUC-7322 was considerably more potent for bladder relaxation than atrial beating rate or tracheal relaxation in the monkey, whereas, if anything, the opposite was true for isoprenaline (Maruyama et al 2012b).…”

“…In the isolated cynomolgus monkey bladder, both KUC-7322 and isoprenaline were less potent than in the rat, but KUC-7322 remained a full agonist (Maruyama et al 2012b). Similar to the rat studies, KUC-7322 was considerably more potent for bladder relaxation than atrial beating rate or tracheal relaxation in the monkey, whereas, if anything, the opposite was true for isoprenaline (Maruyama et al 2012b). In isolated human bladder, KUC-7322 was slightly less potent than in the monkey bladder and much less potent than in the rat bladder in two independent studies performed against either passive tension of KCl-induced tone but remained a full agonist relative to isoprenaline .…”

Mirabegron in overactive bladder patients: efficacy review and update on drug safety

“…Two other β3 agonists have been reported in the literature: solabegron and ritobegron. Solabegron has been investigated in a phase II trial and has shown good results [Ohlstein et al 2012], whilst ritobegron has not yet been reported in human trials but has been shown to exhibit potent and selective β3 agonist activity in monkeys [Maruyama et al 2012].…”

The Odd Sibling: Features ofβ3-Adrenoceptor Pharmacology

“…For instance, the agonist BRL 37,344 (Nahmias et al, 1991;Liggett, 1992), the weak partial agonist CGP 12,177 (((-)-4-(3-t-butylamino-2-hydroxypropoxy)- [5, H]benzimidazole-2-one) (Liggett, 1992), and the antagonist/ biased agonist L 748,337 (Candelore et al, 1999;van Wieringen et al, 2013) exhibit affinity differences of 10-fold or more between rat and human or rat and rhesus monkey b 3 -adrenoceptors, indicating important species differences in the ligand binding pocket; a better understanding of such difference awaits, resolving the crystal structure of b 3 -adrenoceptors. Based on such species differences, several investigators have turned to monkeys to explore properties of novel b 3 -adrenoceptor agonists (Maruyama et al, 2012;Hatanaka et al, 2013).…”