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Nonpeptide Bradykinin B2 Receptor Antagonists:  Conversion of Rodent-Selective Bradyzide Analogues into Potent, Orally-Active Human Bradykinin B2 Receptor Antagonists 1

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Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BS, England
Cite this: J. Med. Chem. 2002, 45, 11, 2160–2172
Publication Date (Web):April 24, 2002
https://doi.org/10.1021/jm0111088
Copyright © 2002 American Chemical Society
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    Abstract

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    The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid {2-[(2-dimethylaminoethyl)methylamino]ethyl}amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a Ki of 0.5 ± 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 μmol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b−d) with Ki ranges of 10.7−176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79−253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 μmol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.

    *

     To whom correspondence should be addressed. Tel.:  0044(0)20 7333 2167. Fax:  0044(0)20 7387 4116. E-mail:  ed.dziadulewicz@ pharma.novartis.com.

    †

     Present address:  Novartis Pharmaceuticals Corp., 556 Morris Avenue, Summit, NJ 07901.

    ‡

     Present address:  Pfizer Global Research and Development, 3-9 Rue de la Loge, Fresnes Cedex 94265, France.

    §

     Present address:  Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, England.

    ‖

     Present address:  Packard, Brook House, 14 Station Road, Pangbourne, Berkshire RG8 7AN, England.

    ⊥

     Present address:  Pfizer Central Research, Sandwich, Kent CT13 9NJ, England.

    #

     Present address:  AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville Saint-Laurent, Québec H4S 1Z9, Canada.

    ∇

     Present address:  Celltech R&D Ltd., 208 Bath Road, Slough, Berkshire SL1 3WE, England.

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    2. Yuki Sawada,, Hiroshi Kayakiri,, Yoshito Abe,, Keisuke Imai,, Tsuyoshi Mizutani,, Noriaki Inamura,, Masayuki Asano,, Ichiro Aramori,, Chie Hatori,, Akira Katayama,, Teruo Oku, and, Hirokazu Tanaka. A New Series of Highly Potent Non-Peptide Bradykinin B2 Receptor Antagonists Incorporating the 4-Heteroarylquinoline Framework. Improvement of Aqueous Solubility and New Insights into Species Difference. Journal of Medicinal Chemistry 2004, 47 (7) , 1617-1630. https://doi.org/10.1021/jm030159x
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    4. Cecylia S. Lupala, Patricia Gomez-Gutierrez, Juan J. Perez. New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding. Journal of Molecular Graphics and Modelling 2016, 68 , 184-196. https://doi.org/10.1016/j.jmgm.2016.06.010
    5. Cecylia S. Lupala, Patricia Gomez-Gutierrez, Juan J. Perez. New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding. Journal of Computer-Aided Molecular Design 2016, 30 (1) , 85-101. https://doi.org/10.1007/s10822-015-9890-z
    6. H P Rang. Pharmacology. 2013, 157-170. https://doi.org/10.1016/B978-0-7020-4299-7.00011-1
    7. János Éles, Gyula Beke, István Vágó, Éva Bozó, József Huszár, Ákos Tarcsay, Sándor Kolok, Éva Schmidt, Mónika Vastag, Katalin Hornok, Sándor Farkas, György Domány, György M. Keserű. Quinolinyl- and phenantridinyl-acetamides as bradykinin B1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 2012, 22 (9) , 3095-3099. https://doi.org/10.1016/j.bmcl.2012.03.065
    8. . References. 2010, 917-970. https://doi.org/10.1016/B978-0-08-095843-9.00018-5
    9. József Huszár, Zoltán Timár, Ferenc Bogár, Botond Penke, Róbert Kiss, Krisztina Katalin Szalai, Éva Schmidt, Andrea Papp, György Keserű. Aspartic acid scaffold in bradykinin B1 antagonists. Journal of Peptide Science 2009, 15 (6) , 423-434. https://doi.org/10.1002/psc.1134
    10. József Huszár, Zoltán Timár, Krisztina Katalin Szalai, György Keserű, Ferenc Fülöp, Botond Penke. Novel bradykinin-1 antagonists containing a (1,2,3,4-tetrahydro-isoquinolin-1-yl)acetic acid scaffold. European Journal of Medicinal Chemistry 2008, 43 (7) , 1552-1558. https://doi.org/10.1016/j.ejmech.2007.10.030
    11. B.A. Trofimov, N.A. Nedolya. Pyrroles and their Benzo Derivatives: Reactivity. 2008, 45-268. https://doi.org/10.1016/B978-008044992-0.00302-3
    12. Takeshi Isoda, Kazuhiko Hayashi, Satoshi Tamai, Toshio Kumagai, Yoshimitsu Nagao. Efficient Synthesis of Isothiocyanates Based on the Tandem Staudinger/aza-Wittig Reactions and Mechanistic Consideration of the Tandem Reactions. Chemical and Pharmaceutical Bulletin 2006, 54 (11) , 1616-1619. https://doi.org/10.1248/cpb.54.1616
    13. Edward K Dziadulewicz. Non-peptide ligands for bradykinin receptors 1995 – 2004. Expert Opinion on Therapeutic Patents 2005, 15 (7) , 829-859. https://doi.org/10.1517/13543776.15.7.829
    14. L. M. Fredrik Leeb-Lundberg, Francois Marceau, Werner Müller-Esterl, Douglas J. Pettibone, Bruce L. Zuraw. International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences. Pharmacological Reviews 2005, 57 (1) , 27-77. https://doi.org/10.1124/pr.57.1.2
    15. Guillaume Morissette, Jean-Philippe Fortin, Sophie Otis, Johanne Bouthillier, François Marceau. A Novel Nonpeptide Antagonist of the Kinin B 1 Receptor: Effects at the Rabbit Receptor. Journal of Pharmacology and Experimental Therapeutics 2004, 311 (3) , 1121-1130. https://doi.org/10.1124/jpet.104.071266
    16. François Marceau, Domenico Regoli. Bradykinin receptor ligands: therapeutic perspectives. Nature Reviews Drug Discovery 2004, 3 (10) , 845-852. https://doi.org/10.1038/nrd1522
    17. Edward K. Dziadulewicz. Bradykinin B2 Receptor Antagonists for the Treatment of Pain. 2004, 111-124. https://doi.org/10.1016/S0065-7743(04)39009-3
    18. François Marceau, Jean-Philippe Fortin, Guillaume Morissette, Edward K. Dziadulewicz. A non-peptide antagonist unusually selective for the human form of the bradykinin B2 receptor. International Immunopharmacology 2003, 3 (10-11) , 1529-1536. https://doi.org/10.1016/S1567-5769(03)00180-2
    19. Mark G. Bock, J.Fred Hess, Douglas J. Pettibone. Chapter 12. Bradykinin-1 receptor antagonists. 2003, 111-120. https://doi.org/10.1016/S0065-7743(03)38013-3
    20. R. G. Hill, K. R. Oliver. Neuropeptide and Kinin Antagonists. , 181-216. https://doi.org/10.1007/978-3-540-33823-9_7
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