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

  • J Med Chem. 2024 Feb 8;67(3):2049-2065. doi: 10.1021/acs.jmedchem.3c01562.
Ann M Rowley  1 ,  Gang Yao  2 ,  Logan Andrews  3 ,  Aaron Bedermann  1 ,  Ross Biddulph  4 ,  Ryan Bingham  4 ,  Jennifer J Brady  3 ,  Rachel Buxton  4 ,  Ted Cecconie  1 ,  Rona Cooper  1 ,  Adam Csakai  2 ,  Enoch N Gao  1 ,  Melissa C Grenier-Davies  2 ,  Meghan Lawler  2 ,  Yiqian Lian  1 ,  Justyna Macina  4 ,  Colin Macphee  4 ,  Lisa Marcaurelle  2 ,  John Martin  1 ,  Patricia McCormick  1 ,  Rekha Pindoria  4 ,  Martin Rauch  1 ,  Warren Rocque  1 ,  Yingnian Shen  1 ,  Lisa M Shewchuk  1 ,  Michael Squire  1 ,  Will Stebbeds  4 ,  Westley Tear  2 ,  Xin Wang  3 ,  Paris Ward  1 ,  Shouhua Xiao  3
Affiliations
  • 1. GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 2. GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States.
  • 3. 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States.
  • 4. GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K.
PMID: 38284310 DOI: 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.

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