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  1. Article ; Online: Building a Culture of Medicinal Chemistry Knowledge Sharing.

    Beshore, Douglas C / Haidle, Andrew M / Arasappan, Ashok / Lim, Yeon-Hee / Raheem, Izzat / Roecker, Anthony J / Shockley, Samantha E / Simov, Vladimir

    Journal of medicinal chemistry

    2022  Volume 65, Issue 5, Page(s) 3776–3785

    Abstract: Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this ... ...

    Abstract Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at Merck & Co. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.
    MeSH term(s) Chemistry, Pharmaceutical ; Drug Discovery
    Language English
    Publishing date 2022-02-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c02144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    Roecker, Anthony J / Cox, Christopher D / Coleman, Paul J

    Journal of medicinal chemistry

    2016  Volume 59, Issue 2, Page(s) 504–530

    Abstract: Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the ...

    Abstract Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.
    MeSH term(s) Animals ; Dogs ; Humans ; Hypnotics and Sedatives/chemical synthesis ; Hypnotics and Sedatives/pharmacology ; Mice ; Models, Molecular ; Narcolepsy/drug therapy ; Orexin Receptor Antagonists/pharmacology ; Orexin Receptor Antagonists/therapeutic use ; Orexin Receptors/drug effects ; Rats ; Sleep Initiation and Maintenance Disorders/drug therapy
    Chemical Substances Hypnotics and Sedatives ; Orexin Receptor Antagonists ; Orexin Receptors
    Language English
    Publishing date 2016-01-28
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.5b00832
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings.

    VanHeyst, Michael D / Qi, Ji / Roecker, Anthony J / Hughes, Jonathan M E / Cheng, Lili / Zhao, Zheyu / Yin, Jingjun

    Organic letters

    2020  Volume 22, Issue 4, Page(s) 1648–1654

    Abstract: Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C( ... ...

    Abstract Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp
    Language English
    Publishing date 2020-01-28
    Publishing country United States
    Document type Journal Article
    ISSN 1523-7052
    ISSN (online) 1523-7052
    DOI 10.1021/acs.orglett.0c00242
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings

    VanHeyst, Michael D / Cheng, Lili / Hughes, Jonathan M. E / Qi, Ji / Roecker, Anthony J / Yin, Jingjun / Zhao, Zheyu

    Organic letters. 2020 Jan. 28, v. 22, no. 4

    2020  

    Abstract: Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)–C(sp3) cross-coupling of these fragments to afford ... ...

    Abstract Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)–C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.
    Keywords chemical structure ; cross-coupling reactions ; organic halogen compounds ; pentane ; physicochemical properties ; salts
    Language English
    Dates of publication 2020-0128
    Size p. 1648-1654.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1523-7052
    DOI 10.1021/acs.orglett.0c00242
    Database NAL-Catalogue (AGRICOLA)

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  5. Article: Discovery of [

    Perkins, James J / McQuade, Paul / Bungard, Christopher J / Diamond, Tracy L / Gantert, Liza T / Gotter, Anthony L / Hanney, Barbara / Hills, Ivory D / Hurzy, Danielle M / Joshi, Aniket / Kern, Jonathan T / Schlegel, Kelly-Ann S / Manikowski, Jesse J / Meng, Zhaoyang / O'Brien, Julie A / Roecker, Anthony J / Smith, Sean M / Uslaner, Jason M / Hostetler, Eric /
    Meissner, Robert S

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 7, Page(s) 986–992

    Abstract: Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator ( ... ...

    Abstract Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR
    Language English
    Publishing date 2023-06-13
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00175
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Orexin receptor antagonists: medicinal chemistry and therapeutic potential.

    Roecker, Anthony J / Coleman, Paul J

    Current topics in medicinal chemistry

    2008  Volume 8, Issue 11, Page(s) 977–987

    Abstract: Actelion Pharmaceuticals achieved clinical proof-of-concept for the treatment of insomnia in 2007 with the release of Phase II data on Almorexant, a potent dual (OX1R/OX2R) orexin receptor antagonist. GlaxoSmithKline also released clinical efficacy data ... ...

    Abstract Actelion Pharmaceuticals achieved clinical proof-of-concept for the treatment of insomnia in 2007 with the release of Phase II data on Almorexant, a potent dual (OX1R/OX2R) orexin receptor antagonist. GlaxoSmithKline also released clinical efficacy data on an orexin receptor antagonist in 2007 for the treatment of insomnia. With these exciting findings, the search for orexin (or hypocretin) receptor antagonists for the treatment of sleep and neurological disorders has recently increased in intensity in the pharmaceutical industry. This review will focus on the medicinal chemistry of orexin antagonists and the potential therapeutic value of this therapy for the treatment of insomnia. Receptor subtype selectivity will also be described to highlight the tools currently available to delineate receptor-specific pharmacology.
    MeSH term(s) Humans ; Hypnotics and Sedatives/chemistry ; Hypnotics and Sedatives/pharmacology ; Hypnotics and Sedatives/therapeutic use ; Molecular Structure ; Orexin Receptors ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, Neuropeptide/antagonists & inhibitors ; Sleep Initiation and Maintenance Disorders/drug therapy ; Structure-Activity Relationship
    Chemical Substances HCRTR2 protein, human ; Hypnotics and Sedatives ; Orexin Receptors ; Receptors, G-Protein-Coupled ; Receptors, Neuropeptide
    Language English
    Publishing date 2008-07-24
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/156802608784936746
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5572: Show issues Location:
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  7. Article ; Online: Discovery of dual orexin receptor antagonists (DORAs) for the treatment of insomnia.

    Coleman, Paul J / Cox, Christopher D / Roecker, Anthony J

    Current topics in medicinal chemistry

    2011  Volume 11, Issue 6, Page(s) 696–725

    Abstract: Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in ... ...

    Abstract Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity.
    MeSH term(s) Animals ; Drug Discovery ; Humans ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacokinetics ; Indoles/pharmacology ; Orexin Receptors ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Neuropeptide/antagonists & inhibitors ; Receptors, Neuropeptide/metabolism ; Sleep Initiation and Maintenance Disorders/drug therapy ; Sleep Initiation and Maintenance Disorders/metabolism ; Spiro Compounds/chemical synthesis ; Spiro Compounds/chemistry ; Spiro Compounds/pharmacokinetics ; Spiro Compounds/pharmacology ; Structure-Activity Relationship ; Tetrahydroisoquinolines/chemical synthesis ; Tetrahydroisoquinolines/chemistry ; Tetrahydroisoquinolines/pharmacokinetics ; Tetrahydroisoquinolines/pharmacology
    Chemical Substances Indoles ; Orexin Receptors ; Receptors, G-Protein-Coupled ; Receptors, Neuropeptide ; Spiro Compounds ; Tetrahydroisoquinolines
    Language English
    Publishing date 2011-01-14
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 2064823-6
    ISSN 1873-4294 ; 1568-0266
    ISSN (online) 1873-4294
    ISSN 1568-0266
    DOI 10.2174/1568026611109060696
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve.

    Klein, Rebecca M / Layton, Mark E / Regan, Hillary / Regan, Christopher P / Li, Yuxing / Filzen, Tracey / Cato, Matt / Clements, Michelle K / Wang, Jixin / Sanoja, Raul / Greshock, Thomas J / Roecker, Anthony J / Pero, Joseph E / Kim, Ron / Burgey, Christopher / John, Christopher T / Wang, Ying-Hong / Bhandari, Neetesh / Struyk, Arie /
    Kraus, Richard L / Henze, Darrell A / Houghton, Andrea K

    Channels (Austin, Tex.)

    2022  Volume 16, Issue 1, Page(s) 230–243

    Abstract: As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents ... ...

    Abstract As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function.
    MeSH term(s) Animals ; NAV1.7 Voltage-Gated Sodium Channel ; Pain ; Phrenic Nerve ; Rats ; Respiratory Insufficiency/drug therapy
    Chemical Substances NAV1.7 Voltage-Gated Sodium Channel
    Language English
    Publishing date 2022-10-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2262854-X
    ISSN 1933-6969 ; 1933-6969
    ISSN (online) 1933-6969
    ISSN 1933-6969
    DOI 10.1080/19336950.2022.2122309
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

    Loughran, H Marie / Schirripa, Kathy M / Roecker, Anthony J / Breslin, Michael J / Tong, Ling / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Newman, Justin A / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Flick, Rosemarie B / Liu, Xiaomei / Minnick, Christina / Watt, Marla L /
    Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

    ACS medicinal chemistry letters

    2023  Volume 15, Issue 1, Page(s) 123–131

    Abstract: Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing ...

    Abstract Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead
    Language English
    Publishing date 2023-12-21
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00436
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

    Roecker, Anthony J / Schirripa, Kathy M / Loughran, H Marie / Tong, Ling / Liang, Tao / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Hatcher, Nathan G / Yao, Lihang / Kandebo, Monika / Vardigan, Joshua D / Flick, Rosemarie B /
    Liu, Xiaomei / Minnick, Christina / Price, Laura A / Watt, Marla L / Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 2, Page(s) 146–155

    Abstract: Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme ... ...

    Abstract Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with
    Language English
    Publishing date 2023-01-12
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.2c00441
    Database MEDical Literature Analysis and Retrieval System OnLINE

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