Structure activity relationships leading to the identification of the indirect activator of AMPK, R419. (1st October 2022)

• Record Type: Journal Article
• Authors: Shaw, Simon J.; Goff, Dane A.; Carroll, David C.; Singh, Rajinder; Sweeny, David J.; Park, Gary; Jenkins, Yonchu; Markovtsov, Vadim; Sun, Tian-Qiang; Issakani, Sarkiz D.; Hitoshi, Yasumichi; Payan, Donald G.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 71(2022)
• Publication Date: 2022-10-01
• Subjects: AMPK -- Diabetes -- R419 -- Mitochondria -- Structure activity relationships -- hERG; %F bioavailability -- ACC phospho-acetyl-CoA carboxylase -- ADP adenosine diphosphate -- AICAR 5-aminoimidazole-4-carboxamide ribonucleotide -- AMP adenosine monophosphate -- AMPK 5′-adenosine monophosphate activated protein kinase -- ATP adenosine triphosphate -- AUC area under the curve -- Boc benzyloxycarbonyl -- CaMKKβ calcium/calmodulin-dependent protein kinase kinase β -- CYP cytochrome P450 -- DAST (diethylamino)sulfur trifluoride -- DIO diet induced obesity -- EC50 half maximal effective concentration -- GLUT4 glucose transporter type 4 -- HATU 1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate -- hERG human ether-a-go-go related gene -- HFD high fat diet -- mCPBA meta-chloroperoxybenzoic acid -- IC50 half maximal inhibitory concentration -- LKB1 liver kinase B1 -- OGGT oral glucose tolerance test -- PK pharmacokinetic -- SAR structure activity relationship -- t½ half-life -- ULK UNC-51-like kinase -- ZMP 5-aminoimidazole-4-carboxamide ribonucleotide monophosphate; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116951
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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).