Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.
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Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors.
Bioorg Med Chem Lett
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Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble β-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.
View Article and Find Full Text PDFA-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors.
Bioorg Med Chem Lett
February 2013
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.
View Article and Find Full Text PDFStructure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors.
Bioorg Med Chem Lett
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Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
View Article and Find Full Text PDFDiscovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.
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Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
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