A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
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Pyrazole-based arylalkyne cathepsin S inhibitors. Part III: modification of P4 region.
Bioorg Med Chem Lett
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Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
Novel classes of tetrahydropyrido-pyrazole thioether amines and arylalkynes that display potency against human Cathepsin S have been previously reported. Here, key pharmacophoric elements of these two classes are merged, and SAR investigations of the P4 region are described, in conjunction with re-optimization of the P5 and P1/P1'/P3 regions. Identification of meta-substituted arylalkynes with good potency and improved solubility is described.
View Article and Find Full Text PDFDiscovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions.
Bioorg Med Chem Lett
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Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.
View Article and Find Full Text PDFDiscovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.
Bioorg Med Chem Lett
April 2010
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
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