title: β3-Adrenoceptor agonists for overactive bladder syndrome: Role of translational pharmacology in a repositioning clinical drug development project.
abstract: β3-Adrenoceptor agonists were originally considered as a promising drug class for the treatment of obesity and/or type 2 diabetes. When these development efforts failed, they were repositioned for the treatment of the overactive bladder syndrome. Based on the example of the β3-adrenoceptor agonist mirabegron, but also taking into consideration evidence obtained with ritobegron and solabegron, we discuss challenges facing a translational pharmacology program accompanying clinical drug development for a first-in-class molecule. Challenges included generic ones such as ligand selectivity, species differences and drug target gene polymorphisms. Challenges that are more specific included changing concepts of the underlying pathophysiology of the target condition while clinical development was under way; moreover, a paucity of public domain tools for the study of the drug target and aspects of receptor agonists as drugs had to be addressed. Nonetheless, a successful first-in-class launch was accomplished. Looking back at this translational pharmacology program, we conclude that a specifically tailored and highly flexible approach is required. However, several of the lessons learned may also be applicable to translational pharmacology programs in other indications.
authors.affiliation: Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany. Electronic address: marmiche@uni-mainz.de.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.affiliation: Department of Drug Discovery Science & Management-Europe, Astellas Pharma Europe R&D, Leiden, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: Korstanje
mesh_terms: D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D058492:Drug Repositioning; D006801:Humans; D008024:Ligands; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000502:physiology*; D013577:Syndrome; D057170:Translational Research, Biomedical; D001743:Urinary Bladder / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000906:Antibodies; D008024:Ligands; D022702:Receptors, Adrenergic, beta-3
keywords: Drug development; Mirabegron; Species differences; Translational pharmacology; Urinary bladder; β(3)-Adrenoceptor