Discovery of 7-Bromo-3,4-dihydro-2H-isoquinolin-1-one

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

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.

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Reference：
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem