ACS Medicinal Chemistry Letters · 2010 · 183 citations · 13 references
Pharmaceutical SciencePharmacotherapyPharmaceutical ChemistryMedicinal ChemistryAlzheimer's DiseaseBioanalysis193-Fold SelectivityNeurologyNeurochemistryNovel TherapyBiochemistrySelective γ-Secretase InhibitorPharmacological AgentNeuropharmacologyNeuroprotectionDrug DevelopmentPharmacologyNatural SciencesCarboxamide-substituted SulfonamidesNeuroscienceMedicineDrug Discovery
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
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