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

  • Bioorg Med Chem. 2022 Oct 1:71:116951. doi: 10.1016/j.bmc.2022.116951.
Simon J Shaw  1 ,  Dane A Goff  2 ,  David C Carroll  2 ,  Rajinder Singh  2 ,  David J Sweeny  2 ,  Gary Park  2 ,  Yonchu Jenkins  2 ,  Vadim Markovtsov  2 ,  Tian-Qiang Sun  2 ,  Sarkiz D Issakani  2 ,  Yasumichi Hitoshi  2 ,  Donald G Payan  2
Affiliations
  • 1. Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States. Electronic address: [email protected].
  • 2. Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 35973281 DOI: 10.1016/j.bmc.2022.116951
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).

Keywords
AMPK; Diabetes; Mitochondria; R419; Structure activity relationships; hERG.