Publications by authors named "Emily M Stocking"

13 Publications

  • Page 1 of 1

Structure based design and synthesis of novel Toll-like Receptor 2 (TLR 2) lipid antagonists.

Bioorg Med Chem Lett 2021 May 23;40:127861. Epub 2021 Feb 23.

Neuropore Therapies Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA. Electronic address:

Toll-like receptors (TLRs) play key role in innate immune response to Damage Associated Molecular Patterns (DAMPs) and Pathogen Associated Molecular Patterns (PAMPs). DAMP/PAMP-mediated activation of TLRs triggers NFκB signaling resulting in pro-inflammatory cytokine release. Using TLR2-Pam2CSK4 agonist co-crystal structure information, we designed and synthesized a novel series of Toll-like Receptor 2 (TLR2) lipid antagonists and identified compounds 14, 15 and 17 with sub-micromolar potency. TLR2 antagonists that we identified are stable for > 1.0 h in both gastric juice and PBS buffer and could be used as research tools.
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http://dx.doi.org/10.1016/j.bmcl.2021.127861DOI Listing
May 2021

Synthesis of a histamine H(3) receptor antagonist-manipulation of hydroxyproline stereochemistry, desymmetrization of homopiperazine, and nonextractive sodium triacetoxyborohydride reaction workup.

J Org Chem 2010 Jul;75(13):4463-71

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

We have recently completed the synthesis of 1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, a hydroxyproline-based H(3) receptor antagonist, on 100 g scale. The synthesis proceeds through four steps and route selection was driven by a desire to minimize the cost-of-goods. Naturally occurring trans-4-hydroxy-L-proline was chosen as the precursor to the target's core, which necessitated an inversion at both stereogenic centers. The inversions were accomplished through strategic employment of La Rosa's lactone and a late-stage Mitsunobu reaction. A first generation synthesis that employed N-Boc-homopiperazine was improved in a second generation approach wherein homopiperazine was directly desymmetrized. Finally, the water solubility of a key intermediate necessitated the development of a nonextractive workup for the sodium triacetoxyborohydride reduction.
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http://dx.doi.org/10.1021/jo100629zDOI Listing
July 2010

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2010 May 20;20(9):2755-60. Epub 2010 Mar 20.

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

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H(3) receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H(3) receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
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http://dx.doi.org/10.1016/j.bmcl.2010.03.071DOI Listing
May 2010

Exploration of structure-activity relationships for dual serotonin transporter reuptake inhibitors-histamine H3 receptor antagonists.

Curr Top Med Chem 2010 ;10(5):596-616

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

Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.
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http://dx.doi.org/10.2174/156802610791111515DOI Listing
September 2010

Histamine H3 antagonists as wake-promoting and pro-cognitive agents.

Curr Top Med Chem 2008 ;8(11):988-1002

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

The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.
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http://dx.doi.org/10.2174/156802608784936728DOI Listing
October 2008

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Jan 13;18(1):39-43. Epub 2007 Nov 13.

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

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2007.11.016DOI Listing
January 2008

Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Sep 26;17(17):4799-803. Epub 2007 Jun 26.

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

The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H(3) ligands that are also serotonin reuptake transporters is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.061DOI Listing
September 2007

Synthesis and biological evaluation of diamine-based histamine H3 antagonists with serotonin reuptake inhibitor activity.

Bioorg Med Chem Lett 2007 Jun 15;17(11):3130-5. Epub 2007 Mar 15.

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

The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.034DOI Listing
June 2007

Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 16;17(4):1047-51. Epub 2006 Nov 16.

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

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.036DOI Listing
February 2007

Identification of novel inhibitors of bacterial translation elongation factors.

Antimicrob Agents Chemother 2005 Jan;49(1):131-6

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

Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in polypeptide chain elongation in protein biosynthesis. A novel scintillation proximity assay for the detection of inhibitors of EF-Tu and EF-Ts, as well as the interaction between them, was developed and used in a high-throughput screen of a chemical library. Several compounds from a variety of chemical series with inhibitory properties were identified, including certain indole dipeptides, benzimidazole amidines, 2-arylbenzimidazoles, N-substituted imidazoles, and N-substituted guanidines. The in vitro activities of these compounds were confirmed in a coupled bacterial transcription-translation assay. Several indole dipeptides were identified as inhibitors of bacterial translation, with compound 2 exhibiting a 50% inhibitory concentration of 14 microM and an MIC for S. aureus ATCC 29213 of 5.6 microg/ml. Structure-activity relationship studies around the dipeptidic indoles generated additional analogs with low micromolar MICs for both gram-negative and gram-positive bacteria. To assess the specificity of antibacterial action, these compounds were evaluated in a metabolic labeling assay with Staphylococcus aureus. Inhibition of translation, as well as limited effects on other macromolecular pathways for some of the analogs studied, indicated a possible contribution from a non-target-based antibacterial mechanism of action.
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http://dx.doi.org/10.1128/AAC.49.1.131-136.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC538871PMC
January 2005

Chemistry and biology of biosynthetic Diels-Alder reactions.

Angew Chem Int Ed Engl 2003 Jul;42(27):3078-115

Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.

Nature's repertoire of biosynthetic transformations has recently been recognized to include the Diels-Alder cycloaddition reaction. Evidence now exists that there are enzymes that mediate the Diels-Alder reaction in secondary metabolic biosynthetic pathways. 2002 marked the 100th anniversary of Alder's birth and 75 years since the discovery of the Diels-Alder reaction. It would appear that living systems discovered and made use of this ubiquitously useful ring-forming reaction eons ago for the construction of complex natural products. In this Review an overview is given of all of the known classes of natural products (polyketides, isoprenoids, phenylpropanoids, alkaloids) that have been speculated to arise by a biological Diels-Alder reaction.
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http://dx.doi.org/10.1002/anie.200200534DOI Listing
July 2003

Reverse versus Normal Prenyl Transferases in Paraherquamide Biosynthesis Exhibit Distinct Facial Selectivities.

Angew Chem Int Ed Engl 1999 Mar;38(6):786-789

Department of Chemistry Colorado State University, Fort Collins, Colorado 80523 (USA), Fax: (+1) 970-491-5610.

Both a face-selective and a non-face-selective mode of formation of quaternary centers of isoprene-derived structural moieties of the natural alkaloid paraherquamide A (1) have been discovered by feeding experiments on Penicillium fellutanum with [U- C ]-glucose and [ C ]-acetate. The labeling patterns suggest that the methyl groups (C22, C23) are introduced in a non-face-selective manner by a reverse prenyl transferase. The C unit comprising the dioxepin moiety retains stereochemical integrity indicative of a single, face-selective addition of the phenolic group to the dimethylallyl group.
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http://dx.doi.org/10.1002/(SICI)1521-3773(19990315)38:6<786::AID-ANIE786>3.0.CO;2-7DOI Listing
March 1999