Syntheses and Pharmacological Properties of the Histaminic H 1 Antagonists Sila-terfenadine-A, Sila-terfenadine-B, Disila-terfenadine, and Sila-fexofenadine: A Study on C/Si Bioisosterism Reinhold Tacke,* ,† Thomas Schmid, † Martin Penka, † Christian Burschka, † William Bains, ‡ and Julie Warneck ‡ Institut fu ¨ r Anorganische Chemie, Universita ¨ t Wu ¨ rzburg, Am Hubland, D-97074 Wu ¨ rzburg, Germany, and Amedis Pharmaceuticals Ltd., 162 Cambridge Science Park, Milton Road, Cambridge CB4 0GP, U.K. Received June 8, 2004 Sila-substitution (C/Si exchange) of one or both of the two quaternary carbon atoms of the histaminic H 1 antagonist terfenadine (1a) leads to sila-terfenadine-A (1b;R 3 COH f R 3 SiOH), sila-terfenadine-B (1c;R 4 C f R 4 Si), or disila-terfenadine (1d;R 3 COH f R 3 SiOH, R 4 C f R 4 Si). Sila-substitution of the quaternary carbon atom of the histaminic H 1 antagonist fexofenadine (2a) affords sila-fexofenadine (2b;R 3 COH f R 3 SiOH). The silicon compounds rac-1b, rac-1c, rac-1d, and rac-2b were synthesized in multistep syntheses, and the identities of these compounds and their precursors were established by elemental analyses and multinuclear NMR studies. Some of the precursors were additionally characterized by single- crystal X-ray diffraction. The pharmacological profiles of rac-1a, rac-1b, rac-1c, rac-1d, rac- 2a, and rac-2b were assessed across a range of histaminic receptor binding assays (radioligand binding studies at histamine central H 1 , peripheral H 1 ,H 2 , and H 3 receptors). The silicon compounds, within experimental error, exhibited an affinity and selectivity profile similar to their corresponding carbon analogues. Introduction Histaminic H 1 antagonists were utilized for the first time in the 1940s for the treatment of allergic disorders. Clinically, these antihistamines were used to alleviate the symptoms of various allergic conditions. These relatively nonselective agents also possessed significant anticholinergic activity, which enabled their utility in treating motion sickness and as adjunct therapy for the amelioration of Parkinsonism. Unfortunately, the seda- tive side-effects of the classic histaminic H 1 antagonists were immense, and the search for sedation-free H 1 receptor antagonists finally led to the clinical introduc- tion of terfenadine (1a), 1 which became the world’s leading nonsedating antihistamine in 1994. However, soon it turned out that terfenadine can cause severe cardiovascular side effects. 2 As opposed to this, the actual pharmacologically active compound, the carbox- ylic acid metabolite of terfenadine, fexofenadine (2a), 3 does not show such side effects. Therefore, the nonse- dating histaminic H 1 antagonist fexofenadine itself was introduced to the market as a clinical replacement for terfenadine with an improved safety profile. The car- diovascular side effects of terfenadine were subse- quently attributed to its affinity for the hERG ion channel, which fexofenadine was shown not to affect. In connection with our systematic studies on C/Si bioisosterism, 4 we investigated the pharmacological effects of sila-substitution (C/Si exchange) of one or both of the two quaternary carbon atoms in the terfenadine molecule (C 3 COH f C 3 SiOH; C 4 C f C 4 Si). In addition, * To whom correspondence should be addressed. E-mail: r.tacke@mail.uni-wuerzburg.de. † Universita ¨t Wu ¨ rzburg. ‡ Amedis Pharmaceuticals Ltd. (1) (a) Kulshrestha, V. K.; Gupta, P. P.; Turner, P.; Wadsworth, J. Br. J. Clin. Pharmacol. 1978, 6, 25-29. (b) Cheng, H. C.; Woodward, J. K. Drug Dev. Res. 1982, 2, 181-196. (c) Woodward, J. K.; Munro, N. L. Arzneim.-Forsch./Drug Res. 1982, 32 (II), 1154-1156. (d) Carr, A. A.; Meyer, D. R. Arzneim.-Forsch./Drug Res. 1982, 32 (II), 1157- 1159. (e) Connell, J. T. Pharmacotherapy 1985, 5, 201-208. (f) Zhang, M. Q.; ter Laak, A. M.; Timmerman, H. Eur. J. Med. Chem. 1993, 28, 165-173. (2) (a) Rampe, D.; Wible, B.; Brown, A. M.; Dage, R. C. Mol. Pharmacol. 1993, 44, 1240-1245. (b) Yang, T.; Prakash, C.; Roden, D. M.; Snyders, D. J. Br. J. Pharmacol. 1995, 115, 267-274. (c) DuBuske, L. M. Clin. Ther. 1999, 21, 281-295. (d) Delpo ´n, E.; Valenzuela, C.; Tamargo, J. Drug Safety 1999, 21 (Suppl. 1), 11-18. (e) Zu ¨ nkler, B. J.; Ku ¨ hne, S.; Rustenbeck, I.; Ott, T. Br. J. Pharmacol. 2000, 130, 1571-1574. (3) (a) Graul, A.; Castan ˜ er, J. Drugs Future 1996, 21, 1017-1021. (b) Markham, A.; Wagstaff, A. J. Drugs 1998, 55, 269-274. (c) Simpson, K.; Jarvis, B. Drugs 2000, 59, 301-321. (4) Recent publications dealing with C/Si bioisosterism: (a) Tacke, R.; Merget, M.; Bertermann, R.; Bernd, M.; Beckers, T.; Reissmann, T. Organometallics 2000, 19, 3486-3497. (b) Merget, M.; Gu ¨ nther, K.; Bernd, M.; Gu ¨ nther, E.; Tacke, R. J. Organomet. Chem. 2001, 628, 183-194. (c) Tacke, R.; Kornek, T.; Heinrich, T.; Burschka, C.; Penka, M.; Pu ¨ lm, M.; Keim, C.; Mutschler, E.; Lambrecht, G. J. Organomet. Chem. 2001, 640, 140-165. (d) Tacke, R.; Schmid, T.; Burschka, C.; Penka, M.; Surburg, H. Organometallics 2002, 21, 113-120. (e) Tacke, R.; Handmann, V. I.; Kreutzmann, K.; Keim, C.; Mutschler, E.; Lambrecht, G. Organometallics 2002, 21, 3727-3732. (f) Tacke, R.; Handmann, V. I.; Bertermann, R.; Burschka, C.; Penka, M.; Seyfried, C. Organometallics 2003, 22, 916-924. (g) Tacke, R.; Schmid, T.; Hofmann, M.; Tolasch, T.; Francke, W. Organometallics 2003, 22, 370- 372. (h) Schmid, T.; Daiss, J. O.; Ilg, R.; Surburg, H.; Tacke, R. Organometallics 2003, 22, 4343-4346. (i) Heinrich, T.; Burschka, C.; Warneck, J.; Tacke, R. Organometallics 2004, 23, 361-366. (j) Tacke, R.; Heinrich, T.; Bertermann, R.; Burschka, C.; Hamacher, A.; Kassack, M. U. Organometallics, in press. (k) Review: Bains, W.; Tacke, R. Curr. Opin. Drug Discovery Dev. 2003, 6, 526-543. 4915 Organometallics 2004, 23, 4915-4923 10.1021/om040084a CCC: $27.50 © 2004 American Chemical Society Publication on Web 09/02/2004