An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model. Issue 10 (1st June 2018)

• Record Type: Journal Article
• Authors: Price, Daniel J.; Drewry, David H.; Schaller, Lee T.; Thompson, Brian D.; Reid, Paul R.; Maloney, Patrick R.; Liang, Xi; Banker, Periette; Buckholz, Richard G.; Selley, Paula K.; McDonald, Octerloney B.; Smith, Jeffery L.; Shearer, Todd W.; Cox, Richard F.; Williams, Shawn P.; Reid, Robert A.; Tacconi, Stefano; Faggioni, Federico; Piubelli, Chiara; Sartori, Ilaria; Tessari, Michela; Wang, Tony Y.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 10(2018)
• Page Start: 1958
• Page End: 1963
• Publication Date: 2018-06-01
• Subjects: CAMKK2 -- Inhibitor -- Satiety; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.03.034
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.