Cleavable Linker Delivers Increased Solubility of Highly Insoluble Small-Molecule Therapeutics

Keywords

solubility - prodrugs - small-molecule therapeutics

Significance

Solubility is a problem that plagues many small-molecule therapeutics. Few moieties have been able to provide solubility enhancement while maintaining pH stability (ranging from 1.2 to 6.5), lack of permeable, toxic byproducts, or suitable hydrolysis pathways not resulting in immediate drug precipitation or multiple enzymatic interactions. The scope of this paper is broad, and the authors were able to show significant improvement in drug administration without specialty formulation. This technology could strongly influence the ability to administer water-insoluble drugs orally.

Comment

The authors incorporate a cleavable solubility tag to a variety of clinical therapeutics with poor solubility. The moieties can be linked to primary and secondary amides, sulfonamides, alcohols, amines, anilines, and NH-containing heterocycles. The carboxylate or phosphonate groups of i–vii are then hydrolyzed by alkaline phosphatase, a critical enzyme in human intestines, to promote the 1,4– or 1,6-eliminations of the solubility group. This then yields byproducts 1 or 2 and the free, released drug. Their compounds showed marked improvement in oral availability in mice and no permeation of the byproducts across the epithelial cells in vitro.

Publication History

Article published online:
21 November 2024