Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.

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.

Citation

Ann M Rowley, Gang Yao, Logan Andrews, Aaron Bedermann, Ross Biddulph, Ryan Bingham, Jennifer J Brady, Rachel Buxton, Ted Cecconie, Rona Cooper, Adam Csakai, Enoch N Gao, Melissa C Grenier-Davies, Meghan Lawler, Yiqian Lian, Justyna Macina, Colin Macphee, Lisa Marcaurelle, John Martin, Patricia McCormick, Rekha Pindoria, Martin Rauch, Warren Rocque, Yingnian Shen, Lisa M Shewchuk, Michael Squire, Will Stebbeds, Westley Tear, Xin Wang, Paris Ward, Shouhua Xiao. Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library. Journal of medicinal chemistry. 2024 Feb 08;67(3):2049-2065

Mesh Tags

Substances

PMID: 38284310

search → result