Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library
Ann Rowley, Gang Yao, Logan D. Andrews, Aaron A. Bedermann, R. H. Biddulph, Ryan P. Bingham, Jennifer J. Brady, Rachel Buxton, Ted Cecconie, Rona Cooper, Adam Csakai, Enoch Gao, Melissa C. Grenier‐Davies, Meghan Lawler, Yiqian Lian, Justyna Macina, Colin H. Macphee, Lisa A. Marcaurelle, John R. Martin, Patricia McCormick, Rekha Pindoria, M. Rauch, Warren J. Rocque, Yingnian Shen, Lisa M. Shewchuk, Michael D. Squire, W. Stebbeds, Westley Tear, Xin Wang, Paris Ward, Shou-Hua Xiao
Abstract
Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.