An assessment of the genetic toxicology of novel boron-containing therapeutic agents.

Abstract

Boron-containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron-containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti-inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase-4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl-tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram-negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2-year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron-based therapeutic agents with no genetic toxicology liabilities.

• Authors: Vic Ciaravino, Jacob Plattner, Sanjay Chanda
• Journal: Environmental and molecular mutagenesis (Environ Mol Mutagen) Vol. 54 Issue 5 Pg. 338-46 (Jun 2013) ISSN: 1098-2280 [Electronic] United States
• PMID: 23625818 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)borane
• Anti-Bacterial Agents
• Antifungal Agents
• Boranes
• Boron Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Pyridines
• DNA
• tavaborole
• crisaborole

Topics

• Animals
• Anti-Bacterial Agents (toxicity)
• Antifungal Agents (toxicity)
• Boranes (toxicity)
• Boron Compounds (toxicity)
• Bridged Bicyclo Compounds, Heterocyclic (toxicity)
• Cells, Cultured
• DNA (drug effects)
• Female
• Humans
• Male
• Mice
• Micronucleus Tests
• Molecular Structure
• Mutagenicity Tests
• Pyridines (toxicity)
• Rats
• Rats, Sprague-Dawley