Can Silicon Make an Excellent Drug Even Better? An in vitro and in vivo Head‐to‐Head Comparison between Loperamide and Its Silicon Analogue Sila‐Loperamide

Abstract

Loperamide (1a), an opioid receptor agonist, is in clinical use as an antidiarrheal agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH→R3 SiOH) leads to sila-loperamide (1b). Sila-loperamide was synthesized in a multistep procedure, starting from triethoxyvinylsilane and taking advantage of the 4-methoxyphenyl (MOP) unit as a protecting group for silicon. The in vitro and in vivo pharmacokinetic (PK) and pharmacodynamic (PD) properties of the C/Si analogues 1a and 1b were determined and compared. Despite significant differences in the in vitro PK properties of loperamide and sila-loperamide regarding clearance, permeability, and efflux, both compounds exhibited nearly identical in vivo PK profiles. The increase in metabolic stability of the silicon compound 1b observed in vitro seems to be counterbalanced by an increase in efflux and diminished permeability compared to the parent carbon compound 1a. Overall, sila-loperamide exhibits high unbound clearance (CLu ), leading to a significant decrease in unbound concentration (Cu ) and unbound area under the curve (AUCu ) after oral exposure, compared to loperamide. In vitro and in vivo metabolic studies showed an altered profile of biotransformation for the silicon compound 1b, leading to the formation of a more polar and quickly cleared metabolite and preventing the formation of the silicon analogue of the neurotoxic metabolite observed for the parent carbon compound 1a. These differences can be correlated with the different chemical properties of the C/Si analogues 1a and 1b. This study provides some of the most detailed insights into the effects of a carbon/silicon switch and how this carbon/silicon exchange affects overall drug properties.

Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

“…Metabolic stability in human and male Han Wistar rat hepatocytes : Hepatocyte metabolic stability was determined in accordance with the method described by Jacobson et al …”

“…In vivo rat PK was assessed as previously described . The studies were approved by the Göteborg Animal Research Ethical Board.…”

“…Solubility: [45] This method measures the thermodynamic solubility of research compounds based on as hake-flask approach. [47] Metabolic stability in human and male Han Wistar rat hepatocytes: [48] Hepatocyte metabolic stability was determined in accordance with the method described by Jacobson et al [49] Intrinsic permeability across Caco-2 cell monolayers:Am onolayer of Caco-2 cells was used to study the permeability in the apical to basolateral direction.…”

Syntheses and crystal structures of 2-methyl-1,1,2,3,3-pentaphenyl-2-silapropane and 2-methyl-1,1,3,3-tetraphenyl-2-silapropan-2-ol

“…The addition of the benzhydryl group to a drug significantly increases its lipophilicity and the two aromatic rings add electron density and bulk. There is an active field looking at the switching of silicon for carbon to discover new medicinal compounds and there have been several recent publications and reviews in the area (Franz & Wilson, 2013;Geyer et al, 2015;Ramesh & Reddy, 2018;Tacke & Doerrich, 2016). It seemed to us that another option is to replace the sulfoxide group with a silanol, in which the silicon has a size that is similar to sulfur and the alcohol will occupy the space of the sulfoxide oxygen.…”

Recent advances in Cu-catalyzed C(sp3)–Si and C(sp3)–B bond formation

“…On the other hand, the trigonal planar nature of boron can lead to dative bond formation with enzymes, and therefore increase binding affinity. As shown in Scheme 1, several silicon [9][10][11][12] and boron-containing [13][14][15][16] drugs have already entered the market, or are currently in the drug development pipeline. As the number of drugs containing these functional groups continues to increase, new synthetic pathways for their inclusion will surely attract synthetic organic chemists, as well challenge them to consider both existing approaches and developing new reactions.…”