Publications by authors named "Alice Lee-Dutra"

9 Publications

  • Page 1 of 1

Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.

Bioorg Med Chem Lett 2013 Feb 5;23(3):811-5. Epub 2012 Dec 5.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).
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http://dx.doi.org/10.1016/j.bmcl.2012.11.074DOI Listing
February 2013

Azabenzthiazole inhibitors of leukotriene A₄ hydrolase.

Bioorg Med Chem Lett 2012 Dec 17;22(24):7504-11. Epub 2012 Oct 17.

Janssen Research & Development LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 μM.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.036DOI Listing
December 2012

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

Indole- and benzothiophene-based histamine H3 antagonists.

Bioorg Med Chem Lett 2010 Nov 27;20(21):6226-30. Epub 2010 Aug 27.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, United States.

Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7-substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model.
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http://dx.doi.org/10.1016/j.bmcl.2010.08.103DOI Listing
November 2010

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

2-Aryl benzimidazoles featuring alkyl-linked pendant alcohols and amines as inhibitors of checkpoint kinase Chk2.

Bioorg Med Chem Lett 2007 Dec 4;17(23):6467-71. Epub 2007 Oct 4.

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

A series of benzimidazole compounds containing pendant alcohol and amine moieties was found to be active against checkpoint kinase Chk2. These compounds were prepared to examine a potential hydrogen bond interaction with an active site residue and to investigate replacement of a biaryl linker with an aliphatic system in an effort to improve solubility.
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http://dx.doi.org/10.1016/j.bmcl.2007.09.098DOI Listing
December 2007

Identification of 2-arylbenzimidazoles as potent human histamine H4 receptor ligands.

Bioorg Med Chem Lett 2006 Dec 20;16(23):6043-8. Epub 2006 Sep 20.

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

A series of 2-arylbenzimidazoles was synthesized and found to bind with high affinity to the human histamine H(4) receptor. Structure-activity relationships were investigated through library preparation and evaluation as well as traditional medicinal chemistry approaches, leading to the discovery of compounds with single-digit nanomolar affinity for the H(4) receptor.
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http://dx.doi.org/10.1016/j.bmcl.2006.08.117DOI Listing
December 2006