Silicon drug analogues.

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I don’t normally write about the pharmaceutical industry, but I was intrigued by several posts by Derek Lowe (who does cover this area) on the topic of creating new drugs by deuterating existing ones. Thus he covered the first deuterated drug receiving FDA approval last year, having first reviewed the concept back in 2009. So when someone introduced me to sila-haloperidol, I checked to see if Derek had written about it. Apparently not, so here are a few details.

The idea appears to take a well-known drug, in this case haloperidol and selectively replacing a carbon atom with a silicon atom to form silahaloperidol.[1] The compound was actually reported in 2004 (see data citation 10.5517/cc7yhc0) but its drug-like properties were only reported four years later in 2008. Haloperidol itself has some undesirable side-effects, including those due to the metabolic products of the drug and so there are certainly reasons for trying to reduce these. Here are the main conclusions:

  1. The sila drug shows a significantly higher affinity for hD2 receptors (Table 1).
  2. Silahaloperidol exhibits higher subtype selectivity at dopamine and σ receptors
  3. The substitution by silicon has little effect on physico-chemical profiles
  4. The in-vivo half-life of the sila analogue was 3.6 times shorter (~18 minutes).
  5. An almost three-fold inhibitory effect against CYP3A4 was noted.
  6. The sila-drug displayed “a completely altered metabolic fate while otherwise maintaining a similar pharmacokinetic profile”.

These do seem to add up to a promising route for optimising drug activities. The authors themselves note the “great potential” for drug design. A review in 2017[2] concurs. So along with deuterated drugs, perhaps siladrugs are ones to watch in the future!


  1. R. Tacke, F. Popp, B. Müller, B. Theis, C. Burschka, A. Hamacher, M. Kassack, D. Schepmann, B. Wünsch, U. Jurva, and E. Wellner, "Sila-Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate", ChemMedChem, vol. 3, pp. 152-164, 2008.
  2. R. Ramesh, and D.S. Reddy, "Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds", Journal of Medicinal Chemistry, 2017.

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