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Active Conformation of Seven‐Membered‐Ring Benzolactams as New ACAT Inhibitors: Latent Chirality at N 5 in the 1,5‐Benzodiazepin‐2‐one Nucleus

2011; Wiley; Volume: 18; Issue: 6 Linguagem: Inglês

10.1002/chem.201103264

1521-3765

Hidetsugu Tabata, Naoya Wada, Yuko Takada, Jun Nakagomi, Tomohiro Miike, Hiroaki Shirahase, Tetsuta Oshitari, Hideyo Takahashi, Hideaki Natsugari,

Asymmetric Synthesis and Catalysis

Chemistry – A European JournalVolume 18, Issue 6 p. 1572-1576 Communication Active Conformation of Seven-Membered-Ring Benzolactams as New ACAT Inhibitors: Latent Chirality at N5 in the 1,5-Benzodiazepin-2-one Nucleus† Hidetsugu Tabata, Hidetsugu Tabata School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorNaoya Wada, Naoya Wada School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorYuko Takada, Yuko Takada School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorJun Nakagomi, Jun Nakagomi School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorTomohiro Miike, Tomohiro Miike Kyoto Pharmaceutical Industries, Ltd. 38 Nishinokyo Tsukinowa-cho, Nakakyo-ku, Kyoto 604-8444 (Japan)Search for more papers by this authorDr. Hiroaki Shirahase, Dr. Hiroaki Shirahase Kyoto Pharmaceutical Industries, Ltd. 38 Nishinokyo Tsukinowa-cho, Nakakyo-ku, Kyoto 604-8444 (Japan)Search for more papers by this authorDr. Tetsuta Oshitari, Dr. Tetsuta Oshitari School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorProf. Dr. Hideyo Takahashi, Prof. Dr. Hideyo Takahashi School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorProf. Dr. Hideaki Natsugari, Corresponding Author Prof. Dr. Hideaki Natsugari [email protected] School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this author Hidetsugu Tabata, Hidetsugu Tabata School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorNaoya Wada, Naoya Wada School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorYuko Takada, Yuko Takada School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorJun Nakagomi, Jun Nakagomi School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorTomohiro Miike, Tomohiro Miike Kyoto Pharmaceutical Industries, Ltd. 38 Nishinokyo Tsukinowa-cho, Nakakyo-ku, Kyoto 604-8444 (Japan)Search for more papers by this authorDr. Hiroaki Shirahase, Dr. Hiroaki Shirahase Kyoto Pharmaceutical Industries, Ltd. 38 Nishinokyo Tsukinowa-cho, Nakakyo-ku, Kyoto 604-8444 (Japan)Search for more papers by this authorDr. Tetsuta Oshitari, Dr. Tetsuta Oshitari School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorProf. Dr. Hideyo Takahashi, Prof. Dr. Hideyo Takahashi School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this authorProf. Dr. Hideaki Natsugari, Corresponding Author Prof. Dr. Hideaki Natsugari [email protected] School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728School of Pharmaceutical Sciences, Teikyo University, 1091-1 Midori-ku, Sagamihara, Kanagawa 252-5195 (Japan), Fax: (+81) 426-85-3728Search for more papers by this author First published: 28 December 2011 https://doi.org/10.1002/chem.201103264Citations: 24 † ACAT=acyl-coenzyme A: cholesterol acyltransferase Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract Nitrogen chirality: Potent new ACAT inhibitors with seven-membered-ring benzolactams as the core structures were first prepared, and the axial chirality recognized by the enzyme was clarified (e.g., 1; see scheme). The chirality at the axis (aS) of 1 controls the conformation of the entire lactam ring, causing the N5-CH3 to arrange in a pseudo-equatorial position (i.e., the amine at N5 is a chiral center with the S-configuration) both in the crystal state and in solution. References 1 1aF. Malik, M. Hasan, K. M. Khan, S. Perveen, G. Snatzke, H. Duddeck, W. Voelter, Liebigs Ann. 1995, 1861– 1869; 1bK. M. Khan, F. Malik, M. Hasan, S. Perveen, G. Snatzke, W. Voelter, Z. Naturforsch. 1995, 50b, 1869– 1882; 1cK. M. Khan, F. Malik, G. Snatzke, W. Voelter, Z. Naturforsch. 1996, 51b, 588– 598; 1dM. Hasan, T. A. Nizami, A. Malik, C. Ohlendorf, W. Hiller, W. Voelter, Z. Naturforsch. 1998, 53b, 485– 487. 2J. B. Bariwal, K. D. Upadhyay, A. T. Manvar, J. C. Trivedi, J. S. Singh, K. S. Jain, A. K. Shah, Eur. J. Med. Chem. 2008, 43, 2279– 2290. 3J. W. H. Watthey, J. L. Stanton, M. Desai, J. E. Babiarz, B. M. Finn, J. Med. Chem. 1985, 28, 1511– 1516. 4H. Tabata, N. Wada, Y. Takada, T. Oshitari, H. Takahashi, H. Natsugari, J. Org. Chem. 2011, 76, 5123– 5131. 5For recent review articles on axial chirality and atropisomerism, see: 5aJ. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPlante, Angew. Chem. 2009, 121, 6516– 6520; Angew. Chem. Int. Ed. 2009, 48, 6398– 6401; 5bS. R. LaPlante, L. D. Fader, K. R. Fandrick, D. R. Fandrick, O. Hucke, R. Kemper, S. P. F. Miller, P. J. Edwards, J. Med. Chem. 2011, 54, 7005– 7022. 6For the relation between the axial chirality arising from the sp2–sp2 axis of the benzene–amide bond and biological activity, see: 6aY. Ikeura, T. Doi, A. Fujishima, H. Natsugari, Chem. Commun. 1998, 2141– 2142; 6bY. Ikeura, Y. Ishichi, T. Tanaka, A. Fujishima, M. Murabayashi, M. Kawada, T. Ishimaru, I. Kamo, T. Doi, H. Natsugari, J. Med. Chem. 1998, 41, 4232– 4239; 6cH. Natsugari, Y. Ikeura, I. Kamo, T. Ishimaru, Y. Ishichi, A. Fujishima, T. Tanaka, F. Kasahara, M. Kawada, T. Doi, J. Med. Chem. 1999, 42, 3982– 3993; 6dJ. S. Albert, D. Aharony, D. Andisik, H. Barthlow, P. R. Bernstein, R. A. Bialecki, R. Dedinas, B. T. Dembofsky, D. Hill, K. Kirkland, G. M. Koether, B. J. Kosmider, C. Ohnmacht, W. Palmer, W. Potts, W. Rumsey, L. Shen, A. Shenvi, S. Sherwood, P. J. Warwick, K. Russell, J. Med. Chem. 2002, 45, 3972– 3983; 6eS. D. Guile, J. R. Bantick, M. E. Cooper, D. K. Donald, C. Eyssade, A. H. Ingall, R. J. Lewis, B. P. Martin, R. T. Mohammed, T. J. Potter, R. H. Reynolds, S. A. St-Gallay, A. D. Wright, J. Med. Chem. 2007, 50, 254– 263; 6fJ. Porter, A. Payne, I. Whitcombe, B. de Candole, D. Ford, R. Garlish, A. Hold, B. Hutchinson, G. Trevitt, J. Turner, C. Edwards, C. Watkins, J. Davis, C. Stubberfield, Bioorg. Med. Chem. Lett. 2009, 19, 1767– 1772; 6gH. Takahashi, S. Wakamatsu, H. Tabata, T. Oshitari, A. Harada, K. Inoue, H. Natsugari, Org. Lett. 2011, 13, 760– 763; 6hH. Tabata, J. Nakagomi, D. Morizono, T. Oshitari, H. Takahashi, H. Natsugari, Angew. Chem. 2011, 123, 3131– 3135; Angew. Chem. Int. Ed. 2011, 50, 3075– 3079. 7K. Takahashi, M. Kasai, M. Ohta, Y. Shoji, K. Kunishiro, M. Kanda, K. Kurahashi, H. Shirahase, J. Med. Chem. 2008, 51, 4823– 4833. 8G. Llaverías, J. Laguna, M. Alegret, Cardiovasc. Drug Rev. 2003, 21, 33– 50. 9 9aA. T. Lada, M. Davis, C. Kent, J. Chapman, H. Tomoda, S. Omura, L. L. Rudel, J. Lipid Res. 2004, 45, 378– 386; 9bT. Ohshiro, D. Matsuda, K. Sakai, C. Degirolamo, H. Yagyu, L. L. Rudel, S. Omura, S. Ishibashi, H. Tomoda, Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1108– 1115. 10H. Natsugari, T. Kamide, Jpn. Kokai Tokkyo Koho 2007, JP2007176809. See Supporting Information for the typical lead compounds (I) and their inhibitory activity. 11The assay for the ACAT inhibitory activity shown in Table 1 is that using rabbit liver microsomes, which is regarded as the assay for ACAT-2 isoform. By this assay, the intrinsic enzyme inhibitory activity of the compound is well evaluated. Another assay using esterified cholesterol (EC) accumulation in THP-1 cell-derived macrophages, which is regarded as the assay for ACAT-1 isoform, was also performed. In this EC accumulation assay, a similar pattern of the difference in potency between A (eutomer) and B (distomer) was also observed. See the Supporting Information for details. 12The ΔG≠ value was determined based on the time-dependent conversion rate (% ee) estimated from chiral HPLC analysis of a solution of the enantiomers after allowing them to stand at designated temperatures (see Supporting Information for measurements); see M. Petit, A. J. B. Lapierre, D. P. Curran, J. Am. Chem. Soc. 2005, 127, 14994– 14995. 13Since the distomer B partly isomerizes to the eutomer A (ca. 1–9 %) during the assay period (for 25 min at 37 °C), the intrinsic potency of B is weaker than the data and the difference in potency between A and B may be intrinsically larger than the data obtained (also isomerization from A to B affects the data). See the Supporting Information for the isomerization profiles. 14See the Supporting Information for CD and UV data and spectra. 15CCDC-831103 (2 A), CCDC-831104 (3 A) and CCDC-831105 (4) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. The absolute stereochemistry was determined based on the Flack parameter (CuKα radiation was used for the measurement). 16Note that the definition of axial chirality (aS and aR) leads to reversed stereochemical designations between 2/3 (X=NCH3/S) and 4 (X=CH2) according to the priority rule. The terms aS and aR (chiral axis nomenclature) correspond to P and M (helix nomenclature), respectively. 17See the Supporting Information for the bond angles around the N5-nitrogen in 2 A and 7. 18For review articles on the hydrogen bond, see: 18aT. Steiner, Angew. Chem. 2002, 114, 50– 80; Angew. Chem. Int. Ed. 2002, 41, 48– 76; 18bG. A. Jeffrey, An Introduction to Hydrogen Bonding, Oxford University Press, Oxford, 1997, pp 11– 32. 19Compounds 2′–4′ were shown to exist as a mixture of E- and Z-conformers at the N-CH3 amide moiety in the 1H NMR spectra (ratio: 4.4–5.0:1). See the Supporting Information for details. 20See the Supporting Information for detailed 1H NMR data on 2 A and 2′ A, including a magnified view of the methylene region. 21D. Didier, B. Tylleman, N. Lambert, C. M. L. V. Velde, F. Blockhuys, A. Collas, S. Sergeyev, Tetrahedron 2008, 64, 6252– 6262. 22M. J. Dearden, C. R. Firkin, J.-P. R. Hermet, P. O'Brien, J. Am. Chem. Soc. 2002, 124, 11870– 11871. 23The Cotton effects in the CD spectrum [λnm (Δε)] for 7,[1] 306 (+1.76), 281 (−1.30), 259 (+1.98) (sh), 241 (+3.68), 231 (−5.21), 212 (+3.80), and those for the de-chloro derivative of 7,[1] 299 (+1.74), 270 (−2.05), 237 (+5.26), 226 (−3.10), 211 (+1.75). Citing Literature Supporting Information Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Filename Description chem_201103264_sm_miscellaneous_information.pdf2.6 MB miscellaneous_information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume18, Issue6February 6, 2012Pages 1572-1576 ReferencesRelatedInformation