β3-Adrenoceptor agonists for overactive bladder syndrome: Role of translational pharmacology in a repositioning clinical drug development project

Pharmacology & Therapeutics
Martin C Michel, Cees Korstanje

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...Continue Reading

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Citations

Jun 16, 2017·Journal of Clinical Pharmacology·Marcel van GelderenCees Korstanje
Dec 7, 2017·BJU International·Caoimhin S GriffinGerard P Sergeant
Sep 7, 2018·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Koji Ueshima, Masashi Ukai
Dec 16, 2017·British Journal of Pharmacology·Nodi DehvariDana Sabine Hutchinson
Nov 25, 2018·British Journal of Pharmacology·Massimo Dal MontePaola Bagnoli
Jan 13, 2018·Molecular Pharmacology·Martin C Michel, Steven J Charlton
May 19, 2017·American Journal of Physiology. Renal Physiology·Katerina OkekeMartin C Michel
Feb 10, 2020·International Journal of Urology : Official Journal of the Japanese Urological Association·Martin C Michel
Apr 19, 2019·Cells·Giorgia Schena, Michael J Caplan
Feb 6, 2020·Cells·Marianela Bastías-PérezLaura Herrero
Nov 19, 2019·Neurourology and Urodynamics·Christopher Henry FryMarcus J Drake
May 3, 2019·American Journal of Physiology. Cell Physiology·Zhihui FongGerard P Sergeant
Mar 15, 2019·British Journal of Pharmacology·Yasuhiko IgawaMartin C Michel
Jan 29, 2021·British Journal of Pharmacology·Samantha L SaundersTimothy V Murphy
Mar 2, 2021·Frontiers in Pharmacology·Gabriela Reolon PassosFabiola Zakia Mónica
Mar 5, 2021·The Journal of Pharmacology and Experimental Therapeutics·Shizuo YamadaKazumasa Shinozuka
Sep 22, 2021·International Journal of Urology : Official Journal of the Japanese Urological Association·Shizuo YamadaKazumasa Shinozuka

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