An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model
| Autor: | Tony Y. Wang, Chiara Piubelli, Lee T. Schaller, Pierette Banker, Stefano Tacconi, Paula Selley, Todd W. Shearer, Robert A. Reid, Federico Faggioni, Daniel J. Price, Richard F. Cox, Shawn P. Williams, David H. Drewry, Michela Tessari, Richard G. Buckholz, Patrick R. Maloney, Paul R. Reid, Brian D. Thompson, Xi Liang, Jeffery L. Smith, Octerloney B. McDonald, Ilaria Sartori |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Indoles Clinical Biochemistry Administration Oral Pharmaceutical Science Calcium-Calmodulin-Dependent Protein Kinase Kinase Pharmacology Biochemistry Eating Inhibitory Concentration 50 Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Weight loss Drug Discovery medicine Animals Protein Kinase Inhibitors Molecular Biology CAMKK2 Kinase Organic Chemistry Brain AMPK Hydrogen Bonding Ghrelin Bioavailability 030104 developmental biology chemistry Mutagenesis 030220 oncology & carcinogenesis Molecular Medicine Phosphorylation medicine.symptom Penetrant (biochemical) |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:1958-1963 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2018.03.034 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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