Publications by authors named "Danielle K Wiener"

4 Publications

  • Page 1 of 1

Cathepsin S inhibitors: 2004-2010.

Expert Opin Ther Pat 2011 Mar;21(3):311-37

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Introduction: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases.

Areas Covered: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization.

Expert Opinion: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 - 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.
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http://dx.doi.org/10.1517/13543776.2011.553800DOI Listing
March 2011

Thioether acetamides as P3 binding elements for tetrahydropyrido-pyrazole cathepsin S inhibitors.

Bioorg Med Chem Lett 2010 Apr 8;20(7):2379-82. Epub 2010 Feb 8.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.

A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.
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http://dx.doi.org/10.1016/j.bmcl.2010.01.103DOI Listing
April 2010

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors. Part 2: Modification of P3, P4, and P5 regions.

Bioorg Med Chem Lett 2010 Apr 1;20(7):2375-8. Epub 2010 Feb 1.

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.
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http://dx.doi.org/10.1016/j.bmcl.2010.01.104DOI Listing
April 2010

Discovery and SAR of novel pyrazole-based thioethers as cathepsin S inhibitors: part 1.

Bioorg Med Chem Lett 2010 Apr 28;20(7):2370-4. Epub 2010 Jan 28.

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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http://dx.doi.org/10.1016/j.bmcl.2010.01.108DOI Listing
April 2010