Patricia McGovern

Janssen Research & Development, LLC, Raritan, New Jersey, United States

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Publications (6)13.81 Total impact

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    ABSTRACT: 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. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Dec 2014 · Bioorganic & Medicinal Chemistry Letters
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    ABSTRACT: 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. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Oct 2014 · Bioorganic & Medicinal Chemistry Letters
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    ABSTRACT: 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.
    Full-text · Article · Mar 2011 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: 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.
    Full-text · Article · Jun 2010 · Bioorganic & medicinal chemistry letters
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    ABSTRACT: The histamine H(4) receptor (H(4)R) is the latest identified histamine receptor to emerge as a potential drug target for inflammatory diseases. Animal models are employed to validate this potential drug target. Concomitantly, various H(4)R orthologs have been cloned, including the human, mouse, rat, guinea pig, monkey, pig, and dog H(4)Rs. In this article, we expressed all these H(4)R orthologs in human embryonic kidney 293T cells and compared their interactions with currently used standard H(4)R ligands, including the H(4)R agonists histamine, 4-methylhistamine, guanidinylethyl isothiourea (VUF 8430), the H(4)R antagonists 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ 7777120) and [(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4-methylpiperazine (VUF 6002), and the inverse H(4)R agonist thioperamide. Most of the evaluated ligands display significantly different affinities at the different H(4)R orthologs. These "natural mutants" of H(4)R were used to study ligand-receptor interactions by using chimeric human-pig-human and pig-human-pig H(4)R proteins and site-directed mutagenesis. Our results are a useful reference for ligand selection for studies in animal models of diseases and offer new insights in the understanding of H(4)R-ligand receptor interactions.
    Preview · Article · May 2010 · Molecular pharmacology
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    ABSTRACT: The histamine H4 receptor (H4R) has generated excitement as a potential target for the development of novel anti-inflammatory therapies. However, many of its physiological functions are still being uncovered and the development of new pharmacological tools is crucial to help facilitate this work. Previously, indole and benzimidazole piperazines have been described as potent and selective H4R antagonists. Using this as a starting point we have identified new indole and benzimidazole oxime piperidines as ligands for the H4R. These compounds have a high affinity for the human H4R with Ki values ranging from 17-53 nM. They also have high to moderate affinity for the H4R from mouse, rat, guinea pig, and monkey, but poor affinity for the dog homologue. In addition to the high affinity for the H4R, these compounds also exhibit excellent selectivity against other histamine receptors as well as many other receptor targets. These oxime ligands act as agonists of the human H4R in transfected reporter systems, although the degree of agonism depends on the system utilized. Agonistic activity was also observed in human eosinophils as evidenced by their ability to induce a shape change in these cells, although the degree of agonism ranges from full agonist to partial agonist depending on the test conditions. In contrast to their activity at the human H4R, all of the oxime compounds act as full agonists at the mouse receptor regardless of the test system including the ability to induce a calcium response in mouse bone marrow-derived mast cells. Finally the most selective compound, JNJ 28610244, was shown to induce scratching in mice indicating that it can also function as an agonist in vivo. © 2010 Yu et al, publisher and licensee Dove Medical Press Ltd.
    No preview · Article · Jan 2010 · Journal of Receptor, Ligand and Channel Research