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Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)
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Online ISSN: 1860-7187
December 12, 2012
VIP: 2-Phenoxy-nicotinamides are Potent Agonists for the Bile Acid Receptor GPBAR1 (TGR5)
Rainer E. Martin,* Caterina Bissantz, Olivier Gavelle, Christoph Kuratli, Henrietta Dehmlow, Hans G. F. Richter, Ulrike Obst Sander, Shawn D. Erickson, Kyungjin Kim, Sherrie Lynn Pietranico-Cole, Rubén Alvarez-Sánchez, Christoph Ullmer
The prevalence of type 2 diabetes (T2D) has increased by more than 60% since 1990, and there are now more than 150 million people worldwide suffering from T2D. Current T2D management involves drugs focused on β-cell failure and/or insulin resistance and agents that address incretin deficiency or resistance. A major differentiator for any new-generation treatment are the additional benefits of significant body weight decrease. With the exciting discovery of the bile acid receptor GPBAR1 and its role in many facets of glucose and energy homeostasis through various mechanisms of action, GPBAR1 agonists may be effective in treating both T2D and obesity.
Rainer Martin and fellow Roche scientists accordingly sought to identify novel, small-molecule GPBAR1 agonists that would enable pharmacological proof-of-concept studies. A high-throughput screen of the >106 diverse Roche compounds was undertaken that delivered a novel 2-phenoxy-nicotinamide hit structure of moderate activity. Improvements on this lead involved in-depth SAR studies; novel molecules were prepared with the aim of delivering a first-in-class pharmacological tool to probe the value of GPBAR1 activation. In partnership with computational chemists, the substitution pattern of side chains and spacers between structural subunits was explored, allowing the identification of carefully designed potent single-digit nanomolar molecules against the human receptor. The ultimate result was a high-quality tool compound that combines high activation potency on both the human and mouse receptors, favorable physicochemical properties, and sufficient half-life.
The high potency of this lead compound on the mouse receptor eliminates the need for complex, expensive, and time-consuming humanized knock-in models and serves as an initial tool for further assessment of the biological role of the GPBAR1 receptor for both in vitro and in vivo studies.
Received October 16, 2012; published online December 7, 2012, DOI: 10.1002/cmdc.201200474.