Methotrexate prodrugs sensitive to reactive oxygen species for the improved treatment of rheumatoid arthritis.

Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like HO, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a HO sensitive MTX prodrug.

Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis.

A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of HO proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays.

Dipeptidyl nitriles as human dipeptidyl peptidase I inhibitors.

Using a dipeptide nitrile scaffold we have identified a potent and selective inhibitor of human dipeptidyl peptidase I.

Novel semicarbazide-derived inhibitors of human dipeptidyl peptidase I (hDPPI).

Human dipeptidyl peptidase I (hDPPI, cathepsin C, EC 3.4.14.

Solid-phase synthesis and biological activity of a thioether analogue of conotoxin G1.

A bicyclic thioether analogue of alpha-conotoxin G1, a neurotoxin found in the venom of cone snails, was synthesized on solid phase. Two successive intramolecular on-bead cyclizations between a cysteine residue and a chloroacetylated reduced peptide bond are the key steps in the synthesis. The first reduced peptide bond was introduced by a reductive alkylation with a 9-fluorenylmethoxycarbonyl protected amino aldehyde, and the second by coupling of a dipeptide building block containing an allyloxycarbonyl protected reduced peptide bond.

A solid-phase approach to mouse melanocortin receptor agonists derived from a novel thioether cyclized peptidomimetic scaffold.

The solid-phase synthesis of a novel thioether cyclized peptidomimetic scaffold, displaying functionality at the i to i + 3 positions, is reported. The thioether bridge is formed on-bead by an intramolecular reaction between a chloroacetylated reduced peptide bond and the free thiol from a cysteine. The crude products were obtained in moderate to very high purity.