Publications by authors named "John J M Wiener"

12 Publications

  • Page 1 of 1

Discovery of a Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase with Oral Anti-Inflammatory Activity.

ACS Med Chem Lett 2021 May 5;12(5):782-790. Epub 2021 Apr 5.

Janssen Research & Development, 3210 Merryfield Row, San Diego, California 92121-1126, United States.

Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that plays a critical role in the activation of B cells, macrophages, and osteoclasts. Given the key role of these cell types in the pathology of autoimmune disorders, BTK inhibitors have the potential to improve treatment outcomes in multiple diseases. Herein, we report the discovery and characterization of a novel potent and selective covalent 4-oxo-4,5-dihydro-3-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide BTK inhibitor chemotype. Compound irreversibly inhibits BTK by targeting a noncatalytic cysteine residue (Cys481) for covalent bond formation. Compound is characterized by selectivity for BTK, potent BTK occupancy that is sustained after it is cleared from systemic circulation, and dose-dependent efficacy at reducing joint inflammation in a rat collagen-induced arthritis model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.1c00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155241PMC
May 2021

Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse.

Eur J Pharmacol 2020 Aug 11;880:173171. Epub 2020 May 11.

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

Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173171DOI Listing
August 2020

Accelerating Lead Identification by High Throughput Virtual Screening: Prospective Case Studies from the Pharmaceutical Industry.

J Chem Inf Model 2019 05 13;59(5):2046-2062. Epub 2019 Mar 13.

Discovery Sciences , Janssen Research and Development , Welsh and McKean Roads , Spring House , Pennsylvania 19477 , United States.

At the onset of a drug discovery program, the goal is to identify novel compounds with appropriate chemical features that can be taken forward as lead series. Here, we describe three prospective case studies, Bruton Tyrosine Kinase (BTK), RAR-Related Orphan Receptor γ t (RORγt), and Human Leukocyte Antigen DR isotype (HLA-DR) to illustrate the positive impact of high throughput virtual screening (HTVS) on the successful identification of novel chemical series. Each case represents a project with a varying degree of difficulty due to the amount of structural and ligand information available internally or in the public domain to utilize in the virtual screens. We show that HTVS can be effectively employed to identify a diverse set of potent hits for each protein system even when the gold standard, high resolution structural data or ligand binding data for benchmarking, is not available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.8b00941DOI Listing
May 2019

Pyrazole-based arylalkyne cathepsin S inhibitors. Part III: modification of P4 region.

Bioorg Med Chem Lett 2013 Feb 21;23(4):1070-4. Epub 2012 Dec 21.

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 PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.12.014DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2012.10.036DOI Listing
December 2012

Single R-Group Polymorphisms (SRPs) and R-cliffs: an intuitive framework for analyzing and visualizing activity cliffs in a single analog series.

J Chem Inf Model 2011 May 19;51(5):1122-31. Epub 2011 Apr 19.

Informatics, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. , Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.

We introduce Single R-Group Polymorphisms (SRPs, pronounced 'sharps'), an intuitive framework for analyzing substituent effects and activity cliffs in a single congeneric series. A SRP is a pair of compounds that differ only in a single R-group position. Because the same substituent pair may occur in multiple SRPs in the series (i.e., with different combinations of substituents at the other R-group positions), SRP analysis makes it easy to identify systematic substituent effects and activity cliffs at each point of variation (R-cliffs). SRPs can be visualized as a symmetric heatmap where each cell represents a particular pair of substituents color-coded by the average difference in activity between the compounds that contain that particular SRP. SRP maps offer several advantages over existing techniques for visualizing activity cliffs: 1) the chemical structures of all the substituents are displayed simultaneously on a single map, thus directly engaging the pattern recognition abilities of the medicinal chemist; 2) it is based on R-group decomposition, a natural paradigm for generating and rationalizing SAR; 3) it uses a heatmap representation that makes it easy to identify systematic trends in the data; 4) it generalizes the concept of activity cliffs beyond similarity by allowing the analyst to sort the substituents according to any property of interest or place them manually in any desired order.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ci200054uDOI Listing
May 2011

Scaffold explorer: an interactive tool for organizing and mining structure-activity data spanning multiple chemotypes.

J Med Chem 2010 Jul;53(13):5002-11

Johnson & Johnson Pharmaceutical Research & Development, LLC, Welsh & McKean Roads, Spring House, Pennsylvania 19477, USA.

We introduce Scaffold Explorer, an interactive tool that allows medicinal chemists to define hierarchies of chemical scaffolds and use them to explore their project data. Scaffold Explorer allows the user to construct a tree, where each node corresponds to a specific scaffold. Each node can have multiple children, each of which represents a more refined substructure relative to its parent node. Once the tree is defined, it can be mapped onto any collection of compounds and be used as a navigational tool to explore structure-activity relationships (SAR) across different chemotypes. The rich visual analytics of Scaffold Explorer afford the user a "bird's-eye" view of the chemical space spanned by a particular data set, map any physicochemical property or biological activity of interest onto the individual scaffold nodes, serve as an aggregator for the properties of the compounds represented by these nodes, and quickly distinguish promising chemotypes from less interesting or problematic ones. Unlike previous approaches, which focused on automated extraction and classification of scaffolds, the utility of the new tool rests on its interactivity and ability to accommodate the medicinal chemists' intuition by allowing the use of arbitrary substructures containing variable atoms, bonds, and/or substituents such as those employed in substructure search.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm1004495DOI Listing
July 2010

Recent advances in the design of cathepsin S inhibitors.

Curr Top Med Chem 2010 ;10(7):717-32

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

Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation of the invariant chain, a crucial chaperon which also blocks peptide-binding by MHC II molecules, thereby decreasing antigen presentation to CD4(+) T-cells. Extracellular cathepsin S may also be involved in angiogenesis and initiation and/or maintenance of neuropathic pain by cleavage of the membrane-bound chemokine fractalkine (CX3CL1). Cathepsin S inhibitors have thus been suggested to hold potential as therapeutics for a variety of diseases. The initial development of cathepsin S inhibitors targeted irreversible, covalent inhibitors, but more recently the focus has been on reversible inhibitors, representing both covalent modifiers of the enzyme and, of late, noncovalent inhibitors. This review details advances in cathepsin S inhibitor design as reported in the primary literature since 2006, focusing especially on structure-activity relationships of the various covalent and noncovalent inhibitor series.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/156802610791113432DOI Listing
July 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.
View Article and Find Full Text PDF

Download full-text PDF

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

Total synthesis and structural revision of callipeltoside C.

Angew Chem Int Ed Engl 2008 ;47(19):3568-72

Merck Center for Catalysis, Princeton University, Washington Road, Princeton NJ 08544-1009, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.200800086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694666PMC
May 2008

Tetrahydroindazole inhibitors of bacterial type II topoisomerases. Part 2: SAR development and potency against multidrug-resistant strains.

Bioorg Med Chem Lett 2007 May 6;17(10):2718-22. Epub 2007 Mar 6.

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

We have previously reported a novel class of tetrahydroindazoles that display potency against a variety of Gram-positive and Gram-negative bacteria, potentially via interaction with type II bacterial topoisomerases. Herein are reported SAR investigations of this new series. Several compounds possessing broad-spectrum potency were prepared. Further, these compounds exhibit activity against multidrug-resistant Gram-positive microorganisms equivalent to that against susceptible strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2007.03.004DOI Listing
May 2007

Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis.

Bioorg Med Chem Lett 2007 May 6;17(10):2723-7. Epub 2007 Mar 6.

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

In an attempt to search for a new class of antibacterial agents, we have discovered a series of pyrazole analogs that possess good antibacterial activity for Gram-positive and Gram-negative organisms via inhibition of type II bacterial topoisomerases. We have investigated the structure-activity relationships of this series, with an emphasis on the length and conformation of the linker. This work led to the identification of tetrahydroindazole analogs, such as compound 1, as the most potent class of compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2007.03.003DOI Listing
May 2007
-->