Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity.
This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.
['Kuramoto|Kazuyuki|K|', 'Sawada|Yuki|Y|', 'Yamada|Tomohiro|T|', 'Nagashima|Takeyuki|T|', 'Ohnuki|Kei|K|', 'Shin|Takashi|T|']
D055372:AMP-Activated Protein Kinases D000818:Animals D000970:Antineoplastic Agents D045744:Cell Line, Tumor D049109:Cell Proliferation D004354:Drug Screening Assays, Antitumor D051638:Ether-A-Go-Go Potassium Channels D022781:Hepatocytes D006801:Humans D008297:Male D008325:Mammary Neoplasms, Experimental D051379:Mice D008819:Mice, Nude D008862:Microsomes, Liver D015394:Molecular Structure D051381:Rats D017207:Rats, Sprague-Dawley D012995:Solubility
AMP-activated protein kinase human breast cancer aqueous solubility human ether-a-go-go related gene metabolic stability precision medicine