Talk to the Veterans Crisis Line now
U.S. flag
An official website of the United States government
Veterans Benefits and Health Care About VA Find a VA Location

VA Health Systems Research

Go to the VA ORD website
Go to the QUERI website

HSR&D Citation Abstract

Search | Search by Center | Search by Source | Keywords in Title

Structure activity relationships leading to the identification of the indirect activator of AMPK, R419.

Shaw SJ, Goff DA, Carroll DC, Singh R, Sweeny DJ, Park G, Jenkins Y, Markovtsov V, Sun TQ, Issakani SD, Hitoshi Y, Payan DG. Structure activity relationships leading to the identification of the indirect activator of AMPK, R419. Bioorganic & medicinal chemistry. 2022 Oct 1; 71:116951.

Dimensions for VA is a web-based tool available to VA staff that enables detailed searches of published research and research projects.

If you have VA-Intranet access, click here for more information vaww.hsrd.research.va.gov/dimensions/

VA staff not currently on the VA network can access Dimensions by registering for an account using their VA email address.    Search Dimensions for VA for this citation
* Don't have VA-internal network access or a VA email address? Try searching the free-to-the-public version of Dimensions


Abstract:

Using an in-cell AMPK activation assay, we have developed structure-activity relationships around a hit pyridine dicarboxamide 5 that resulted in 40 (R419). A particular focus was to retain the on-target potency while also improving microsomal stability and reducing off-target activities, including hERG inhibition. We were able to show that removing a tertiary amino group from the piperazine unit of hit compound 5 improved microsomal stability while hERG inhibition was improved by modifying the substitution of the central core pyridine ring. The SAR resulted in 40, which continues to maintain on-target potency. Compound 40 was able to activate AMPK in vivo after oral administration and showed efficacy in animal models investigating activation of AMPK as a therapy for glucose control (both db/db and DIO mouse models).




Questions about the HSR website? Email the Web Team

Any health information on this website is strictly for informational purposes and is not intended as medical advice. It should not be used to diagnose or treat any condition.