Overactive bladder is a condition that reduces the quality of life of millions of people around the world. It is projected to be an increasing burden on an aging population. The primary symptom of an overactive bladder—urinary incontinence—can be controlled with drugs, however, these also cause dry mouth and constipation and, as a result, many patients stop taking them.
A search for treatments with alternative modes of action had previously revealed the β3-adrenergic receptor agonists to be a new class of drug candidates. Building on these earlier studies, Scott Edmonson and colleagues, Merck Research Laboratories, Rahway, NJ, USA, have developed a second generation of such compounds, and optimized one of these—”vibegron”—for phase 3 clinical trials.
The team report a full medicinal chemistry study on a series of compounds and, based on structure-activity data, pharmacokinetics and drug metabolism studies in vitro and in rats, dogs, and monkeys, they propose vibegron as the best-in-class preclinical candidate. Notably, vibegron treatment increased bladder capacity in rats. While they await the results of the human clinical trials, the researchers also provide a preliminary structural model of the interactions of vibegron with its target, the β3-adrenergic receptor.
- Discovery of Vibegron: A Potent and Selective Beta 3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder,
S. D. Edmondson, C. Zhu, N. F. Kar, J. Di Salvo, H. Nagabukuro, B. Sacre-Salem, K. Dingley, R. Berger, S. Goble, G. J. Morriello, B. Harper, C. R. Moyes, D.-M. Shen, L. Wang, R. G. Ball, A. Fitzmaurice, T. Frenkl, L. Gichuru, S. N. Ha, A. Hurley, N. Jochnowitz, D. Levorse, S. Mistry, R. Miller, J. Ormes, G. Salituro, A. Sanfiz, A. Stevenson, K. Villa, B. Zamlynny, S. Green, M. Struthers, A. E. Weber,
J. Med. Chem. 2016.