Synthesis and immunological activity of water-soluble thalidomide prodrugs

A series of new water-soluble thalidomide prodrugs was prepared. All compou nds were derivatized on the nitrogen of the glutarimide ring. Esters of nat ural amino acids and succinic acid derivatives have been introduced by reac tion with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxy methyl deriva tive and a carboxymethyl derivative were prepared directly from thalidomide . Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N- methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respecti vely, were the most soluble compounds showing solubility greater than 300 m g/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k '. The stability of selected compounds was determined. The hydrolysis rates follo w pseudo-first order kinetics. In order to assess the immunological activit y, the prodrugs were tested using tumor necrosis factor-alpha and interleuk in-2 inhibition assays. Selected compounds were additionally investigated o n their abililty to inhibit the local Shwartzman reaction, an assay to dete rmine the Vascular permeability. The prodrugs retained high effectiveness i n the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a hig h affine binding to the pharmacophore. In conclusion, the prodrugs exhibite d high water solubility and high activity and might therefore be used in th erapeutic applications. (C) 2001 Elsevier Science Ltd. All rights reserved.