In Vivo Mutagenicity Testing of Arylboronic Acids and Esters

Area of Science:

• Toxicology
• Medicinal Chemistry
• Genotoxicity Testing

Background:

• Arylboronic compounds are key pharmaceutical synthesis intermediates.
• In vitro mutagenicity tests often yield positive results for these compounds.
• Current regulations control them based on the threshold of toxicological concern (TTC).

Purpose of the Study:

• To evaluate the in vivo relevance of in vitro positive mutagenicity findings for arylboronic compounds.
• To assess the genotoxicity of arylboronic compounds using established in vivo assays.
• To inform regulatory management of arylboronic compounds in pharmaceutical development.

Main Methods:

• Eight arylboronic compounds with diverse scaffolds were tested.
• In vivo assays included Pig-a and comet assays in rats (Sprague Dawley/Wistar).
• Micronucleus assay was performed on five compounds; routes included oral and intravenous administration.

Main Results:

• All tested arylboronic compounds achieved adequate systemic exposure.
• Compounds positive for mutagenicity in vitro were negative in corresponding in vivo assays.
• No in vivo mutagenicity was detected for the tested arylboronic compounds.

Conclusions:

• Arylboronic compounds mutagenic in vitro are not mutagenic in vivo.
• These findings support managing similar arylboronic compounds as non-mutagenic.
• Management can follow ICH Q3A/Q3B guidelines, simplifying pharmaceutical impurity controls.