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.
AbstractHaloperidol (1 a), a dopamine (D2) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila‐substitution) at the 4‐position of the piperidine ring of 1 a (R3COH → R3SiOH) leads to sila‐haloperidol (1 b). Sila‐haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6‐trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D1–D5, σ1, and σ2 receptors. Sila‐haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pKa, solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco‐2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila‐haloperidol (1 b) in human liver microsomes were identified using mass‐spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.