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Syntheses and Pharmacological Properties of the Histaminic H1 Antagonists Sila-terfenadine-A, Sila-terfenadine-B, Disila-terfenadine, and Sila-fexofenadine:  A Study on C/Si Bioisosterism

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journal contribution
posted on 11.10.2004, 00:00 by Reinhold Tacke, Thomas Schmid, Martin Penka, Christian Burschka, William Bains, Julie Warneck
Sila-substitution (C/Si exchange) of one or both of the two quaternary carbon atoms of the histaminic H1 antagonist terfenadine (1a) leads to sila-terfenadine-A (1b; R3COH → R3SiOH), sila-terfenadine-B (1c; R4C → R4Si), or disila-terfenadine (1d; R3COH → R3SiOH, R4C → R4Si). Sila-substitution of the quaternary carbon atom of the histaminic H1 antagonist fexofenadine (2a) affords sila-fexofenadine (2b; R3COH → R3SiOH). 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 H1, peripheral H1, H2, and H3 receptors). The silicon compounds, within experimental error, exhibited an affinity and selectivity profile similar to their corresponding carbon analogues.