An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model.

Autor: Price DJ; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA. Electronic address: daniel.j.price@gsk.com., Drewry DH; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Schaller LT; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA., Thompson BD; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Reid PR; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Maloney PR; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Liang X; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Banker P; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA., Buckholz RG; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA., Selley PK; All Research Described was Performed as Employees of GlaxoSmithKline(c)., McDonald OB; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Smith JL; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Shearer TW; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Cox RF; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Williams SP; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA., Reid RA; GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA., Tacconi S; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Faggioni F; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Piubelli C; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Sartori I; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Tessari M; All Research Described was Performed as Employees of GlaxoSmithKline(c)., Wang TY; All Research Described was Performed as Employees of GlaxoSmithKline(c).
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jun 01; Vol. 28 (10), pp. 1958-1963. Date of Electronic Publication: 2018 Apr 05.
DOI: 10.1016/j.bmcl.2018.03.034
Abstrakt: 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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