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
J. Med. Chem., 2024, XXXX, XXX, XXX-XXX
https://doi.org/10.1021/acs.jmedchem.3c01562

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.