Notice: file_put_contents(): Write of 220498 bytes failed with errno=28 No space left on device in /opt/frankenphp/design.onmedianet.com/app/src/Arsae/CacheManager.php on line 36

Warning: http_response_code(): Cannot set response code - headers already sent (output started at /opt/frankenphp/design.onmedianet.com/app/src/Arsae/CacheManager.php:36) in /opt/frankenphp/design.onmedianet.com/app/src/Models/Response.php on line 17

Warning: Cannot modify header information - headers already sent by (output started at /opt/frankenphp/design.onmedianet.com/app/src/Arsae/CacheManager.php:36) in /opt/frankenphp/design.onmedianet.com/app/src/Models/Response.php on line 20
Discovery of 3-Methyl-N-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘H-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D4 Agonist for the Treatment of Erectile Dysfunction | Journal of Medicinal Chemistry
ACS Publications. Most Trusted. Most Cited. Most Read
Discovery of 3-Methyl-N-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘H-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D4 Agonist for the Treatment of Erectile Dysfunction
Advanced Search
    Article

    Discovery of 3-Methyl-N-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘H-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D4 Agonist for the Treatment of Erectile Dysfunction
    Click to copy article linkArticle link copied!

    View Author Information
    Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500
    Other Access OptionsSupporting Information (1)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2006, 49, 25, 7450–7465
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm060662k
    Published November 10, 2006
    Copyright © 2006 American Chemical Society
    Request reuse permissions

    Abstract

    Click to copy section linkSection link copied!
    Abstract Image

    The goal of this study was to identify a structurally distinct D4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure−activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.

    Copyright © 2006 American Chemical Society

    Subjects

    what are subjects

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. Add or change your institution or let them know you’d like them to include access.

    *

     To whom correspondence should be addressed:  tel +1-847-935-4846; fax +1-847-935-5466; e-mail [email protected].

    Supporting Information Available

    Click to copy section linkSection link copied!

    Elemental analysis data for the compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    Click to copy section linkSection link copied!

    This article is cited by 34 publications.

    1. Fabian Graßl, Leonard Bock, Álvaro Huete-Huerta González, Martin Schiller, Peter Gmeiner, Jörg König, Martin F. Fromm, Harald Hübner, Markus R. Heinrich. Exploring Structural Determinants of Bias among D4 Subtype-Selective Dopamine Receptor Agonists. Journal of Medicinal Chemistry 2023, 66 (14) , 9710-9730. https://doi.org/10.1021/acs.jmedchem.3c00537
    2. Tao Sheng, Hai-Jun Zhang, Ming Shang, Chi He, Julien. C. Vantourout, Phil. S. Baran. Electrochemical Decarboxylative N-Alkylation of Heterocycles. Organic Letters 2020, 22 (19) , 7594-7598. https://doi.org/10.1021/acs.orglett.0c02799
    3. Anna S. Pirzer, Roman Lasch, Heike Friedrich, Harald Hübner, Peter Gmeiner, Markus R. Heinrich. Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity. Journal of Medicinal Chemistry 2019, 62 (21) , 9658-9679. https://doi.org/10.1021/acs.jmedchem.9b01085
    4. Thomas M. Keck, R. Benjamin Free, Marilyn M. Day, Sonvia L. Brown, Michele S. Maddaluna, Griffin Fountain, Charles Cooper, Brooke Fallon, Matthew Holmes, Christopher T. Stang, Russell Burkhardt, Alessandro Bonifazi, Michael P. Ellenberger, Amy H. Newman, David R. Sibley, Chun Wu, Comfort A. Boateng. Dopamine D4 Receptor-Selective Compounds Reveal Structure–Activity Relationships that Engender Agonist Efficacy. Journal of Medicinal Chemistry 2019, 62 (7) , 3722-3740. https://doi.org/10.1021/acs.jmedchem.9b00231
    5. Xiaoshen Ma and Seth B. Herzon . Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer. The Journal of Organic Chemistry 2016, 81 (19) , 8673-8695. https://doi.org/10.1021/acs.joc.6b01709
    6. Navendu Jana, Quyen Nguyen, and Tom G. Driver . Development of a Suzuki Cross-Coupling Reaction between 2-Azidoarylboronic Pinacolate Esters and Vinyl Triflates To Enable the Synthesis of [2,3]-Fused Indole Heterocycles. The Journal of Organic Chemistry 2014, 79 (6) , 2781-2791. https://doi.org/10.1021/jo500252e
    7. NaYe, John L. Neumeyer, Ross J. Baldessarini, XuechuZhen, and Ao Zhang . Update 1 of: Recent Progress in Development of Dopamine Receptor Subtype-Selective Agents: Potential Therapeutics for Neurological and Psychiatric Disorders. Chemical Reviews 2013, 113 (5) , PR123-PR178. https://doi.org/10.1021/cr300113a
    8. N. Jagadeesh Babu,, L. Sreenivas Reddy, and, Ashwini Nangia. Amide−N-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine N-Oxides. Molecular Pharmaceutics 2007, 4 (3) , 417-434. https://doi.org/10.1021/mp070014c
    9. Haibao Zhang, Guodong Zhu, Haomin Ren, Wenbin Song, Zhishang Yang. Comprehensive Perspectives for Erectile Dysfunction Pharmacotherapy: From Mechanism to Application. Current Medicinal Chemistry 2022, 29 (41) , 6276-6287. https://doi.org/10.2174/0929867329666220613125000
    10. Manuel Köckinger, Paul Hanselmann, Dominique M. Roberge, Piero Geotti-Bianchini, C. Oliver Kappe, David Cantillo. Sustainable electrochemical decarboxylative acetoxylation of aminoacids in batch and continuous flow. Green Chemistry 2021, 23 (6) , 2382-2390. https://doi.org/10.1039/D1GC00201E
    11. Gianfabio Giorgioni, Fabio Del Bello, Pegi Pavletić, Wilma Quaglia, Luca Botticelli, Carlo Cifani, Emanuela Micioni Di Bonaventura, Maria Vittoria Micioni Di Bonaventura, Alessandro Piergentili. Recent findings leading to the discovery of selective dopamine D4 receptor ligands for the treatment of widespread diseases. European Journal of Medicinal Chemistry 2021, 212 , 113141. https://doi.org/10.1016/j.ejmech.2020.113141
    12. Igor Voznesensky, Kenneth J. DeLay, Wayne J. G. Hellstrom. Advances in pharmacotherapy for erectile dysfunction and associated cardiac impact. Expert Opinion on Pharmacotherapy 2016, 17 (17) , 2281-2289. https://doi.org/10.1080/14656566.2016.1241766
    13. Ulf Simonsen, Simon Comerma‐Steffensen, Karl‐Erik Andersson. Modulation of Dopaminergic Pathways to Treat Erectile Dysfunction. Basic & Clinical Pharmacology & Toxicology 2016, 119 (S3) , 63-74. https://doi.org/10.1111/bcpt.12653
    14. Valerio Mammoli, Alessandro Bonifazi, Diego Dal Ben, Mario Giannella, Gianfabio Giorgioni, Alessandro Piergentili, Maria Pigini, Wilma Quaglia, Ajiroghene Thomas, Amy H. Newman, Sergi Ferré, Marta Sanchez‐Soto, Thomas M. Keck, Fabio Del Bello. A Novel Class of Dopamine D 4 Receptor Ligands Bearing an Imidazoline Nucleus. ChemMedChem 2016, 11 (16) , 1819-1828. https://doi.org/10.1002/cmdc.201600022
    15. Chad M. Kormos, Moses G. Gichinga, Scott P. Runyon, James B. Thomas, S. Wayne Mascarella, Ann M. Decker, Hernán A. Navarro, F. Ivy Carroll. Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres. Bioorganic & Medicinal Chemistry 2016, 24 (16) , 3842-3848. https://doi.org/10.1016/j.bmc.2016.06.029
    16. Taylor C Peak, Faysal A Yafi, Premsant Sangkum, Wayne JG Hellstrom. Emerging drugs for the treatment of erectile dysfunction. Expert Opinion on Emerging Drugs 2015, 20 (2) , 263-275. https://doi.org/10.1517/14728214.2015.1021682
    17. A. I. Moskalenko, V. I. Boev. Synthesis and chemical transformations of tert-butyl-4-vinyl-3,6-dihydro-2H-pyridine-1-carboxylate. Russian Journal of General Chemistry 2014, 84 (9) , 1683-1688. https://doi.org/10.1134/S1070363214090060
    18. Dinithia Sampson, Xue Y. Zhu, Suresh V.K. Eyunni, Jagan R. Etukala, Edward Ofori, Barbara Bricker, Nazarius S. Lamango, Vincent Setola, Bryan L. Roth, Seth Y. Ablordeppey. Identification of a new selective dopamine D4 receptor ligand. Bioorganic & Medicinal Chemistry 2014, 22 (12) , 3105-3114. https://doi.org/10.1016/j.bmc.2014.04.026
    19. Edward Krzyżak, Berenika Szczęśniak-Sięga, Wiesław Malinka. Synthesis and thermal behaviour of new benzo-1,2-thiazine long-chain aryl-piperazine derivatives. Journal of Thermal Analysis and Calorimetry 2014, 115 (1) , 793-802. https://doi.org/10.1007/s10973-013-3185-1
    20. A. I. Moskalenko, V. I. Boev. Synthesis of N-substituted 4-trimethylstannyl-3,6-dihydro-2H-pyridines as promising synthons in the preparative chemistry of piperidine. Russian Journal of General Chemistry 2013, 83 (12) , 2347-2349. https://doi.org/10.1134/S1070363213120256
    21. Stefan Löber, Harald Hübner, Armin Buschauer, Fabrizio Sanna, Antonio Argiolas, Maria Rosaria Melis, Peter Gmeiner. Novel azulene derivatives for the treatment of erectile dysfunction. Bioorganic & Medicinal Chemistry Letters 2012, 22 (23) , 7151-7154. https://doi.org/10.1016/j.bmcl.2012.09.064
    22. Selim Cellek, Annamaria Giraldi. Challenges in sexual medicine. Nature Reviews Urology 2012, 9 (9) , 537-542. https://doi.org/10.1038/nrurol.2012.134
    23. Tom F. Lue. Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction. 2012, 688-720.e11. https://doi.org/10.1016/B978-1-4160-6911-9.00023-2
    24. L. Labanauskas, R. Mazeikaite, R. Striela, O. Gedrimaite, G. Urbelis, A. Zilinskas. Nucleophilic substitution of the acetoxy group in 3-methylbenzoylaminomethyl acetate. Russian Chemical Bulletin 2011, 60 (8) , 1672-1676. https://doi.org/10.1007/s11172-011-0250-4
    25. Stefan Löber, Harald Hübner, Nuska Tschammer, Peter Gmeiner. Recent advances in the search for D3- and D4-selective drugs: probes, models and candidates. Trends in Pharmacological Sciences 2011, 32 (3) , 148-157. https://doi.org/10.1016/j.tips.2010.12.003
    26. Ibrahim A Abdel-Hamid, Karl-Erik Andersson, Andrea Salonia. Exploration of therapeutic targets for sexual dysfunctions: lessons learned from the failed stories. Expert Opinion on Therapeutic Targets 2011, 15 (3) , 325-340. https://doi.org/10.1517/14728222.2011.551008
    27. John L. Waddington, Colm M. P. O'Tuathaigh, Gary J. Remington. Pharmacology and Neuroscience of Antipsychotic Drugs. 2010, 483-514. https://doi.org/10.1002/9781444327298.ch23
    28. Maarten Albersen, Alan W Shindel, Kuwong B Mwamukonda, Tom F Lue. The future is today: emerging drugs for the treatment of erectile dysfunction. Expert Opinion on Emerging Drugs 2010, 15 (3) , 467-480. https://doi.org/10.1517/14728214.2010.480973
    29. Olaf Prante, Miriam Dörfler, Peter Gmeiner. Dopamine Receptor Subtype-Selective Drugs: D2-Like Receptors. 2010, 101-135. https://doi.org/10.1007/978-1-60327-333-6_5
    30. Natalie Richards, Chris Wayman, Kelly A. Allers. Electrophysiological actions of the dopamine agonist apomorphine in the paraventricular nucleus during penile erection. Neuroscience Letters 2009, 465 (3) , 242-247. https://doi.org/10.1016/j.neulet.2009.08.078
    31. Ronan Depoortère, Laurent Bardin, Michael Rodrigues, Erika Abrial, Monique Aliaga, Adrian Newman-Tancredi. Penile erection and yawning induced by dopamine D2-like receptor agonists in rats: influence of strain and contribution of dopamine D2, but not D3 and D4 receptors. Behavioural Pharmacology 2009, 20 (4) , 303-311. https://doi.org/10.1097/FBP.0b013e32832ec5aa
    32. José Barluenga, María Tomás‐Gamasa, Patricia Moriel, Fernando Aznar, Carlos Valdés. Pd‐Catalyzed Cross‐Coupling Reactions with Carbonyls: Application in a Very Efficient Synthesis of 4‐Aryltetrahydropyridines. Chemistry – A European Journal 2008, 14 (16) , 4792-4795. https://doi.org/10.1002/chem.200800390
    33. David Alagille, Andrei O. Koren, Greg Kudej, Julie Staley, Kelly Cosgrove, John Seibyl, Gilles D. Tamagnan. 6‐[ 123 I]Iodo‐2‐[[4‐(2‐methoxyphenyl) piperazin‐1‐yl]methyl]imidazo[1,2‐ a ]pyridine as potential SPECT agent for imaging dopamine D 4 receptor: synthesis and in vivo evaluation in a nonhuman primate. Journal of Labelled Compounds and Radiopharmaceuticals 2008, 51 (4) , 202-206. https://doi.org/10.1002/jlcr.1500
    34. Heidi L. Fraser, Darrin W. Hopper, Kristina M.K. Kutterer, Aimee L. Crombie. Chapter 6.1 Six-membered ring systems: pyridine and benzo derivatives. 2008, 314-352. https://doi.org/10.1016/S0959-6380(08)80014-1
    Go to
    Get e-Alerts
    Get e-Alerts

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2006, 49, 25, 7450–7465
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm060662k
    Published November 10, 2006
    Copyright © 2006 American Chemical Society
    Request reuse permissions

    Article Views

    2582

    Altmetric

    -

    Citations

    34
    Learn about these metrics

    Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

    Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

    The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.