Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors

Journal of Medicinal Chemistry
Tadashi TerasakaIsao Nakanishi

Abstract

We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1-methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide 1 (K(i)= 7.7 nM), which we recently reported. Structure-based drug design (SBDD) utilizing the crystal structure of the 1/ADA complex was performed in order to obtain structure-activity relationships (SAR) for this type of compound rationally and effectively. To utilize the newly formed hydrophobic space (F2), replacement of the benzimidazole ring of 1 with a n-propyl chain (4b) or a simple phenyl ring (4c) was tolerated in terms of binding activity, and the length of the methylene-spacer was shown to be optimal at two or three. Replacement of an amide with an ether as a linker was also well tolerated in terms of binding activity and moreover improved the oral absorption (6a and 6b). Finally, transformation of indol-1-yl to indol-3-yl resulted in discovery of a novel highly potent and orally bioavailable ADA inhibitor, 1-[(R)-4-(5-(3-(4-chlorophenyl)propoxy)-1-methylindol-3-yl)-1-hydroxy-2-butyl]imidazole-4-carboxamide 8c.

References

Dec 1, 1992·Trends in Pharmacological Sciences·K A RudolphiB B Fredholm
Nov 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·A FilippiniM V Sitkovsky
Oct 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·D L MarquardtS I Wasserman
Jan 1, 1994·Journal of Applied Physiology·B N Cronstein
Oct 8, 1993·Science·D G Alberg, S L Schreiber
Aug 1, 1997·Immunology Today·R Resta, L F Thompson
Apr 29, 1998·Immunological Reviews·R FrancoJ Blanco
Apr 29, 1998·Immunological Reviews·C Morimoto, S F Schlossman
Feb 27, 2001·Medicinal Research Reviews·G CristalliE Camaioni
Aug 13, 2002·Cancer Chemotherapy and Pharmacology·Chetan LathiaLloyd Whitfield

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Citations

Jan 4, 2007·Journal of Molecular Modeling·Grzegorz KoczykLeszek Rychlewski
Jan 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Vittorio LimongelliMichele Parrinello
Oct 27, 2009·PLoS Computational Biology·Wesley C Van VoorhisLance J Stewart
Apr 4, 2014·Journal of Cheminformatics·Stefan BietzMatthias Rarey
Jun 14, 2008·Biochemical and Biophysical Research Communications·Takayoshi KinoshitaIsao Nakanishi
Jul 12, 2005·Current Opinion in Chemical Biology·Shawn P WilliamsKenneth H Pearce
Jan 31, 2006·Biochemical Pharmacology·François Franceschi, Erin M Duffy
Jun 17, 2014·Medicinal Research Reviews·Antoni CortésVicent Casadó
Feb 24, 2018·Frontiers in Aging Neuroscience·Soghra BagheriAli A Saboury
Nov 11, 2017·Chemistry : a European Journal·Haixia WangHaiming Guo
Dec 25, 2009·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michael KleinMorten Grøtli
Jun 27, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·Maria Stefania SinicropiFrancesco Menichini
Jan 9, 2015·Preparative Biochemistry & Biotechnology·Ladawan Nakchum, Sang Moo Kim
Jan 6, 2021·Journal of Biomolecular Structure & Dynamics·Pushyaraga P Venugopal, Debashree Chakraborty
Feb 27, 2009·Journal of Chemical Information and Modeling·Takahiro KosugiKazuo Kitaura
Jan 28, 2015·Journal of Chemical Information and Modeling·Wenbo YuAlexander D MacKerell
Dec 9, 2010·Journal of Medicinal Chemistry·Irina Gillerman, Bilha Fischer

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