| Literature DB >> 29653895 |
Daniel J Price1, David H Drewry2, Lee T Schaller3, Brian D Thompson2, Paul R Reid2, Patrick R Maloney2, Xi Liang2, Periette Banker3, Richard G Buckholz3, Paula K Selley2, Octerloney B McDonald2, Jeffery L Smith2, Todd W Shearer2, Richard F Cox2, Shawn P Williams3, Robert A Reid3, Stefano Tacconi2, Federico Faggioni2, Chiara Piubelli2, Ilaria Sartori2, Michela Tessari2, Tony Y Wang2.
Abstract
Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake.Entities:
Keywords: CAMKK2; Inhibitor; Satiety
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Year: 2018 PMID： 29653895 DOI： 10.1016/j.bmcl.2018.03.034
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823