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Novel GSK3 inhibitors_pyridines_BOMCL-10231019-Final.pdf (752.66 kB)
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Discovery and Optimization of Novel Pyridines as Highly Potent and Selective Glycogen Synthase Kinase 3 Inhibitors

preprint
submitted on 29.10.2019 and posted on 31.10.2019 by Savithri Ramurthy, Keith B. Pfister, Rustum S. Boyce, Sean P. Brown, Abran Q. Costales, Manoj Desai, Eric Fang, Barry H. Levine, Simon C. Ng, John M. Nuss, David B. Ring, Cynthia M. Shafer, Wei Shu, Sharada Subramanian, Allan S. Wagman, Haixia Wang, Dirksen Bussiere
Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-beta in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.

History

Email Address of Submitting Author

dirksen.bussiere@novartis.com

Institution

Novartis Institutes for BioMedical Research

Country

United States of America

ORCID For Submitting Author

0000-0002-5623-5648

Declaration of Conflict of Interest

All authors were at one time employees of Chiron Corporation and/or Novartis Institutes for BioMedical Research

Version Notes

Version 1 of preprint

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