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

Autor:	Rowley AM; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Yao G; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Andrews L; 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States., Bedermann A; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Biddulph R; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Bingham R; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Brady JJ; 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States., Buxton R; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Cecconie T; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Cooper R; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Csakai A; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Gao EN; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Grenier-Davies MC; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Lawler M; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Lian Y; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Macina J; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Macphee C; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Marcaurelle L; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Martin J; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., McCormick P; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Pindoria R; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Rauch M; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rocque W; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Shen Y; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Shewchuk LM; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Squire M; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Stebbeds W; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, Hertfordshire, U.K., Tear W; GSK, Encoded Library Technologies, NCE Molecular Discovery, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, United States., Wang X; 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States., Ward P; GSK, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States., Xiao S; 23andMe Inc, Therapeutics, 349 Oyster Point Boulevard, South San Francisco, California 94080, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Feb 08; Vol. 67 (3), pp. 2049-2065. Date of Electronic Publication: 2024 Jan 29.
DOI:	10.1021/acs.jmedchem.3c01562
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu