Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors

  • Bioorg Med Chem Lett. 2020 Feb 15;30(4):126930. doi: 10.1016/j.bmcl.2019.126930.
Savithri Ramurthy  1 ,  Keith B Pfister  2 ,  Rustum S Boyce  3 ,  Sean P Brown  4 ,  Abran Q Costales  5 ,  Manoj C Desai  6 ,  Eric Fang  7 ,  Barry H Levine  8 ,  Simon C Ng  9 ,  John M Nuss  10 ,  David B Ring  11 ,  Cynthia M Shafer  12 ,  Wei Shu  2 ,  Sharadha Subramanian  13 ,  Allan S Wagman  14 ,  Haixia Wang  15 ,  Dirksen E Bussiere  16
Affiliations
  • 1. HiberCell, Inc., 619 West 54th Street, New York, NY 10019, USA.
  • 2. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, USA.
  • 3. Vermont Biosynthetics LLC, 365 Glinnis Road, Northfield, VT 05663, USA.
  • 4. Proneurotech, 161 Oyster Point Blvd., Suite 200, South San Francisco, CA 94080, USA.
  • 5. Chevron Oronite Company LLC, 100 Chevron Way, Richmond, CA 94801, USA.
  • 6. Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 7. Protein Sciences, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, USA.
  • 8. 2026 South Lincoln Avenue, Spokane, WA 99203, USA.
  • 9. 311 Preakness Court, Walnut Creek, CA 94597, USA.
  • 10. Oppilan Pharma, Ltd., 332 Encinitas Blvd., Encinitas, CA 92024, USA.
  • 11. 2375 Cowper Street, Palo Alto, CA 94301, USA.
  • 12. Arcus Biosciences, 3928 Point Eden Way, Hayward, CA 94545, USA.
  • 13. 3305 Cydonia Ct., Dublin, CA 94568, USA.
  • 14. Rain Therapeutics Inc., 8000 Jarvis Avenue, Suite 204, Newark, CA 94560, USA.
  • 15. Takeda San Diego Inc., 10410 Science Center Dr., San Diego, CA 92121, USA.
  • 16. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, USA. Electronic address: [email protected].
PMID: 31926786 DOI: 10.1016/j.bmcl.2019.126930
Abstract

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-β in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.

Keywords
Diabetes; GSK3-β; Structure-based drug design.