title: Pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in cynomolgus monkeys.
abstract: Mirabegron is a novel β3-adrenoceptor agonist developed for the treatment of overactive bladder. To clarify the relationship between the pharmacological effects of mirabegron in monkeys and the clinical efficacy in patients with overactive bladder, the effect of mirabegron on bladder function was evaluated using cynomolgus monkeys. Quantitative PCR revealed that mRNA expression of β3-adrenoceptors was most abundant (98 %) among β-adrenoceptor subtypes in the bladder of cynomolgus monkeys. Mirabegron, which showed selective and potent agonistic activity on monkey β3-adrenoceptors expressed in Chinese hamster ovary cells with EC50 value of 32 nmol/L and intrinsic activity of 0.8, induced concentration-dependent relaxation of bladder smooth muscle strips isolated from cynomolgus monkeys with EC50 values of 120 nmol/L in 20 mmol/L KCl stimulation and 43 nmol/L under 9.81 mN resting tension. In conscious cynomolgus monkeys, mirabegron decreased micturition frequency at oral doses of 1 and 3 mg/kg and increased mean volume voided per micturition at an oral dose of 3 mg/kg. Plasma concentration at which bladder function improved in the cynomolgus monkeys was similar to that at the clinically effective dose in patients with overactive bladder. These data suggest that the relaxant function in monkey bladder is mainly mediated by β3-adrenoceptors similar to that in the human bladder and mirabegron showed efficacy on the bladder functions of the same parameters in clinical evaluation endpoints.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan, toshiki.hatanaka@astellas.com.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Hatanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Ukai
authors.forename: Mai
authors.initials: M
authors.lastname: Watanabe
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Someya
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
mesh_terms: D000083:Acetanilides / Q000097:blood / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; D013844:Thiazoles; D000242:Cyclic AMP; C520025:mirabegron