Publications by authors named "James P Edwards"

54 Publications

A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.

Bioorg Med Chem Lett 2020 11 29;30(22):127589. Epub 2020 Sep 29.

Discovery Chemistry, Janssen Pharmaceutical Research & Development, 1400 McKean Rd, Spring House, PA 19477, USA. Electronic address:

Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bmcl.2020.127589DOI Listing
November 2020

Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.

Cell Chem Biol 2020 12 3;27(12):1500-1509.e13. Epub 2020 Sep 3.

Medicinal Chemistry, Janssen (China) Research & Development Center, Shanghai 201210, China. Electronic address:

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.
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http://dx.doi.org/10.1016/j.chembiol.2020.08.010DOI Listing
December 2020

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

Optimization and biological evaluation of thiazole-bis-amide inverse agonists of RORγt.

Bioorg Med Chem Lett 2020 06 21;30(12):127205. Epub 2020 Apr 21.

Janssen Research and Development, LLC, San Diego, CA 92121, USA. Electronic address:

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with small molecule therapeutics. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We recently described the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole scaffold. Herein we describe the successful optimization of this class by incorporation of an additional amide moiety at the 4-position of the thiazole core. In several optimization cycles, we have reduced human PXR activation, improved solubility, and increased potency while maintaining nuclear receptor selectivity. X-ray crystallographic analysis of compound 1g bound in the sterol binding site of the ligand binding domain of RORγt was largely consistent with an earlier structure, guiding further insight into the molecular mechanism for RORγt inhibition with this series. Compound 1g is orally bioavailable, potent in a human whole blood assay and proved to be efficacious in an ex-vivo IL-17A assay, and was selected for preclinical evaluation.
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http://dx.doi.org/10.1016/j.bmcl.2020.127205DOI Listing
June 2020

Discovery and optimization of new oxadiazole substituted thiazole RORγt inverse agonists through a bioisosteric amide replacement approach.

Bioorg Med Chem Lett 2020 06 7;30(12):127174. Epub 2020 Apr 7.

Janssen Research and Development, LLC, San Diego, CA 92121, USA. Electronic address:

Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.
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http://dx.doi.org/10.1016/j.bmcl.2020.127174DOI Listing
June 2020

Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease.

J Med Chem 2020 03 16;63(6):2915-2929. Epub 2020 Mar 16.

Janssen Research and Development, 3210 Merryfield Row, San Diego, California 92121, United States.

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01439DOI Listing
March 2020

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor.

Pharmacol Res Perspect 2020 02 13;8(1):e00559. Epub 2020 Jan 13.

Janssen Pharmaceutical R&D, LLC. San Diego CA USA.

Phosphoinositide 3-kinases, delta (PI3Kδ) and gamma (PI3Kγ) are enriched in immune cells and regulate the development and function of innate and adaptive immunity. Dual PI3Kδγ inhibitors are considered high value targets for their potential to treat a variety of immune-mediated diseases, but their discovery has been challenging. Here we describe the preclinical pharmacology of HM5023507, an orally active dual inhibitor of δγ isoforms in immune signaling. HM5023507 inhibited PI3Kδ and PI3Kγ isoforms with greater than 100-fold selectivity against PI3Kα and PI3Kβ in recombinant enzymatic assays and in primary human immune cells with an exquisite selectivity against other targets. HM5023507 attenuated the PI3Kδ/γ signaling in human basophils (IC: 42/340 nmol/L; selectivity ratio ~1:8). HM5023507 attenuated the activation and function of human B and T cells, Th17 differentiation of CD4 T cells in the blood of healthy donors and rheumatoid arthritis patients, and cytokine and IgG production in human T and B cell cocultures, in vitro. Orally dosed HM5023507 attenuated PI3K δ/γ-mediated immune signaling in the rat in a dose-related manner. In addition, HM5023507 inhibited semiestablished collagen-induced arthritic inflammation in the rats (ED of 0.25mg/kg, p.o. BID or 0.5 mg/kg, QD, AUC: 1422 ng/mL*h), improved histopathology- and micro-computed tomography (µCT)-based indices of joint damage, bone destruction, and attenuated the levels of anti-collagen antibody, with an overall anti-inflammatory profile matching that of a TNFα neutralizing antibody. The PI3K δγ inhibitory profile of HM5023507 and its selectivity make it a useful tool to further delineate immunobiology of dual PI3K δγ targeting.
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http://dx.doi.org/10.1002/prp2.559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957347PMC
February 2020

Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors.

J Med Chem 2019 05 8;62(10):4936-4948. Epub 2019 May 8.

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

An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.
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http://dx.doi.org/10.1021/acs.jmedchem.8b02014DOI Listing
May 2019

3-Substituted Quinolines as RORγt Inverse Agonists.

Bioorg Med Chem Lett 2019 06 12;29(12):1463-1470. Epub 2019 Apr 12.

Discovery Product Development and Supply, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States.

We have previously reported the syntheses of a series of 3,6-disubstituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). These molecules are potent binders but are high molecular weight and they exhibited poor solubility at pH 2 and pH 7. This manuscript details our efforts at improving physical chemical properties for this series of compounds by increasing the diversity at the 3-position (i.e. introducing heteroatoms and lowering the molecular weight). These efforts have led to molecules which are potent binders with improved solubility.
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http://dx.doi.org/10.1016/j.bmcl.2019.04.021DOI Listing
June 2019

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

Minisci-Photoredox-Mediated α-Heteroarylation of N-Protected Secondary Amines: Remarkable Selectivity of Azetidines.

Org Lett 2018 10 25;20(19):6003-6006. Epub 2018 Sep 25.

Janssen Research and Development, Division of Janssen-Cilag S.A. , Chaussée du Vexin , Val de Reuil 27100 Cedex , France.

The development of a general, mild, and functional-group-tolerant direct functionalization of N-heteroarenes by C-H functionalization with N-protected amines, including azetidines under Minisci-mediated photoredox conditions, is reported. A broad scope of substituted azetidines, including spirocyclic derivatives, and heterocycles were explored. This reaction enables the production of sp3-rich complex druglike structures in one step from unactivated feedstock amines and heterocycles.
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http://dx.doi.org/10.1021/acs.orglett.8b00991DOI Listing
October 2018

Integral transforms of the quantum mechanical path integral: Hit function and path-averaged potential.

Phys Rev E 2018 Apr;97(4-1):042114

Instituto de Física y Matemáticas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio C-3, Apdo. Postal 2-82, C.P. 58040, Morelia, Michoacán, Mexico.

We introduce two integral transforms of the quantum mechanical transition kernel that represent physical information about the path integral. These transforms can be interpreted as probability distributions on particle trajectories measuring respectively the relative contribution to the path integral from paths crossing a given spatial point (the hit function) and the likelihood of values of the line integral of the potential along a path in the ensemble (the path-averaged potential).
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http://dx.doi.org/10.1103/PhysRevE.97.042114DOI Listing
April 2018

Identification and biological evaluation of thiazole-based inverse agonists of RORγt.

Bioorg Med Chem Lett 2018 05 3;28(9):1446-1455. Epub 2018 Apr 3.

Phenex Pharmaceuticals AG, Waldhofer Strasse 104, 69123 Heidelberg, Germany.

The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.093DOI Listing
May 2018

6-Substituted quinolines as RORγt inverse agonists.

Bioorg Med Chem Lett 2017 12 16;27(23):5277-5283. Epub 2017 Oct 16.

Discovery Immunology, Janssen Research and Development, LLC, Welsh and McKean Roads, Spring House, PA 19477, United States.

We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.
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http://dx.doi.org/10.1016/j.bmcl.2017.10.027DOI Listing
December 2017

Small-Molecule Targets in Immuno-Oncology.

Cell Chem Biol 2017 Sep;24(9):1148-1160

Discovery Sciences, Janssen Research & Development, 1400 McKean Road, P O Box 776, Spring House, PA 19477, USA.

Advances in understanding the role and molecular mechanisms underlying immune surveillance and control of (pre)malignancies is revolutionizing clinical practice in the treatment of cancer. Presently, multiple biologic drugs targeting the immune checkpoint proteins PD(L)1 or CTLA4 have been approved and/or are in advanced stages of clinical development for many cancers. In addition, combination therapy with these agents and other immunomodulators is being intensively explored with the aim of improving primary response rates or prolonging overall survival. The effectiveness of cancer immunotherapy with biologics is spurring research in alternate approaches including small-molecule-mediated targeting of intracellular pathways modulating the innate and adaptive immune response. This focus of this review is on some of the key intracellular pathways where the development of a small-molecule therapeutic is attractive, tractable, and potentially synergistic with extracellular biologic-mediated immune checkpoint blockade.
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http://dx.doi.org/10.1016/j.chembiol.2017.08.019DOI Listing
September 2017

Identification and structure activity relationships of quinoline tertiary alcohol modulators of RORγt.

Bioorg Med Chem Lett 2017 05 21;27(9):2047-2057. Epub 2017 Feb 21.

Discovery Immunology, Janssen Research and Development, Welsh and McKean Roads, Spring House, PA 19477, United States. Electronic address:

A high-throughput screen of the ligand binding domain of the nuclear receptor retinoic acid-related orphan receptor gamma t (RORγt) employing a thermal shift assay yielded a quinoline tertiary alcohol hit. Optimization of the 2-, 3- and 4-positions of the quinoline core using structure-activity relationships and structure-based drug design methods led to the discovery of a series of modulators with improved RORγt inhibitory potency and inverse agonism properties.
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http://dx.doi.org/10.1016/j.bmcl.2017.02.044DOI Listing
May 2017

Clinical Development of Histamine H Receptor Antagonists.

Handb Exp Pharmacol 2017 ;241:301-320

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

The discovery of the histamine H receptor (HR) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the HR relative to other histamine receptors. The discovery of the selective HR antagonist JNJ 7777120 was vital for showing a role for the HR in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective HR antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another HR antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many HR antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that HR antagonists can be beneficial in treating atopic dermatitis and pruritus.
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http://dx.doi.org/10.1007/164_2016_130DOI Listing
October 2017

A Prospective Virtual Screening Study: Enriching Hit Rates and Designing Focus Libraries To Find Inhibitors of PI3Kδ and PI3Kγ.

J Med Chem 2016 05 28;59(9):4302-13. Epub 2016 Apr 28.

Discovery Sciences and ‡Immunology, Janssen Research & Development , San Diego, California 92121, United States.

Here, we report a high-throughput virtual screening (HTVS) study using phosphoinositide 3-kinase (both PI3Kγ and PI3Kδ). Our initial HTVS results of the Janssen corporate database identified small focused libraries with hit rates at 50% inhibition showing a 50-fold increase over those from a HTS (high-throughput screen). Further, applying constraints based on "chemically intuitive" hydrogen bonds and/or positional requirements resulted in a substantial improvement in the hit rates (versus no constraints) and reduced docking time. While we find that docking scoring functions are not capable of providing a reliable relative ranking of a set of compounds, a prioritization of groups of compounds (e.g., low, medium, and high) does emerge, which allows for the chemistry efforts to be quickly focused on the most viable candidates. Thus, this illustrates that it is not always necessary to have a high correlation between a computational score and the experimental data to impact the drug discovery process.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01974DOI Listing
May 2016

Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators.

Bioorg Med Chem Lett 2015 Feb 23;25(4):956-9. Epub 2014 Dec 23.

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

Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2014.12.027DOI Listing
February 2015

The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.

Bioorg Med Chem Lett 2014 Dec 13;24(23):5489-92. Epub 2014 Oct 13.

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

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2014.10.013DOI Listing
December 2014

Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H₄ receptor antagonists.

J Med Chem 2014 Mar 21;57(6):2429-39. Epub 2014 Feb 21.

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

This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
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http://dx.doi.org/10.1021/jm401727mDOI Listing
March 2014

Coherent spin control by electrical manipulation of the magnetic anisotropy.

Phys Rev Lett 2013 Jan 7;110(2):027601. Epub 2013 Jan 7.

Department of Materials, University of Oxford, Parks Road, Oxford OX1 3PH, United Kingdom.

High-spin paramagnetic manganese defects in polar piezoelectric zinc oxide exhibit a simple, almost axial anisotropy and phase coherence times of the order of a millisecond at low temperatures. The anisotropy energy is tunable using an externally applied electric field. This can be used to control electrically the phase of spin superpositions and to drive spin transitions with resonant microwave electric fields.
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http://dx.doi.org/10.1103/PhysRevLett.110.027601DOI Listing
January 2013

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.
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http://dx.doi.org/10.1016/j.bmcl.2012.12.014DOI Listing
February 2013

Tricyclic aminopyrimidine histamine H4 receptor antagonists.

Bioorg Med Chem Lett 2011 Nov 19;21(21):6577-81. Epub 2011 Aug 19.

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

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
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http://dx.doi.org/10.1016/j.bmcl.2011.08.014DOI Listing
November 2011

Triamino pyrimidines and pyridines as histamine H(4) receptor modulators.

Bioorg Med Chem Lett 2011 May 30;21(10):3113-6. Epub 2011 Mar 30.

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

Two series of triamino pyrimidines and a series of triamino pyridines have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. Small structural changes in these three hetereoaromatic cores influenced the functional activity of these compounds.
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http://dx.doi.org/10.1016/j.bmcl.2011.03.017DOI Listing
May 2011

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors.

Bioorg Med Chem Lett 2010 Jul 25;20(14):4060-4. Epub 2010 May 25.

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

A pyridazin-4-one fragment 4 (hCatS IC(50)=170 microM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC(50)=430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC(50)=60 nM) and 27 (hCatS IC(50)=40 nM).
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http://dx.doi.org/10.1016/j.bmcl.2010.05.086DOI Listing
July 2010

Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.

Bioorg Med Chem Lett 2010 Jun 11;20(11):3367-71. Epub 2010 Apr 11.

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

The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.017DOI Listing
June 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