Silicon Switches of Marketed Drugs

Pk, Pooni; Ga, Showell

doi:10.2174/138955706778560120

Cited by 105 publications

(26 citation statements)

References 15 publications

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“…One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al, 2008). The present study will focus on a thorough investigation of both phase I and II metabolism of sila-haloperidol compared with those of haloperidol.The use of organosilicon chemistry in drug design has been reviewed previously (Tacke and Linoh, 1989;Bains and Tacke, 2003;Showell and Mills, 2003;Mills and Showell, 2004;Pooni and Showell, 2006;Gately and West, 2007). Carbon and silicon both are group 14 elements and are similar in that they form four covalent bonds with many other elements.…”

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“…The use of organosilicon chemistry in drug design has been reviewed previously (Tacke and Linoh, 1989;Bains and Tacke, 2003;Showell and Mills, 2003;Mills and Showell, 2004;Pooni and Showell, 2006;Gately and West, 2007). Carbon and silicon both are group 14 elements and are similar in that they form four covalent bonds with many other elements.…”

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“…For example, altered bond lengths and angles may change the molecule's interaction with a receptor and hence the pharmacological selectivity and/or potency. Replacing a carbon by a silicon atom may increase the potency of a compound if the carbinol serves as a hydrogen bond donor within the pharmacophore because a silanol is a better hydrogen bond donor than the corresponding carbinol (Bains and Tacke, 2003;Showell and Mills, 2003;Mills and Showell, 2004;Pooni and Showell, 2006).…”

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“…Silicon switches of marketed drugs have recently been reviewed (Pooni and Showell, 2006). The term carbon/silicon switch, also called sila-substitution, is used when a silicon analog of a known drug is synthesized where one carbon atom is replaced by a silicon atom, leaving the rest of the structure unchanged.…”

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“…The term carbon/silicon switch, also called sila-substitution, is used when a silicon analog of a known drug is synthesized where one carbon atom is replaced by a silicon atom, leaving the rest of the structure unchanged. Examples of silicon switches are (besides sila-haloperidol) sila-venlafaxine, sila-fexofenadine, and disila-bexarotene, studied in different in vitro systems (Pooni and Showell, 2006).…”

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In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol.Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...

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In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange

Johansson¹,

Weidolf²,

Popp³

et al. 2009

Drug Metab Dispos

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Organosilicon Compounds, Enzymatic Modification

Zong

Tanaka

Kawamoto

2010

Encyclopedia of Industrial Biotechnology

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Organosilicon compounds play important roles in organic chemistry and pharmaceutical applications. Therefore, increasing attention has been focused on the preparation of organosilicon compounds with desired chemical and physical properties by the effective biocatalysts. This article outlines the bioconversion of organosilicon compounds by the use of biocatalysts such as microorganisms, alcohol dehydrogenases, hydrolases, and hydroxynitrile lyases. The preparation of silicon‐containing amino acids and cyanohydrins by the bioconversion is also described. Furthermore, the effects of silicon atom on the enzymatic reaction are discussed with comparative studies by using organosilicon compounds and corresponding carbon compounds as substrates of enzymes.

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