Synthesis and optimization of hyaluronic acid-methotrexate conjugates to maximize benefit in the treatment of osteoarthritis.

We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage.

Novel hyaluronic acid-methotrexate conjugates for osteoarthritis treatment.

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation.

N-substituent effect on the cis-trans geometry of nine-membered lactams.

The cis-trans geometry of a nine-membered lactam significantly depends on the N-substituents; N-acyl-1-aza-2-cyclononanones (1a-c) exist as cis form; in contrast, N-Z- 1-aza-2-cyclononanone (1d) exists as trans form both in the crystal and in solution.