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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.

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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).

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