CH-1504, being developed by Chelsea Therapeutics Inc under license from the University of South Alabama, is an orally available, metabolically inert antifolate, for the potential treatment of rheumatoid arthritis (RA). CH-1504 is an analog of methotrexate (MTX) but differs from the classical antifolates because of an improved safety and tolerability profile. A significant proportion of the toxicity profile of MTX can be attributed to its polyglutamylated and hydroxylated metabolites; therefore, metabolism-blocked antifolates, such as CH-1504, have been designed to prevent the accumulation of toxic metabolites. Preclinical studies and phase II clinical trials indicated that CH-1504 and MTX inhibit dihydrofolate reductase activity with equal potency. In a phase II, proof-of-concept trial in patients with RA, CH-1504 was associated with improved tolerability and reduced hepatotoxicity as compared with MTX; in addition, improvements in the American College of Rheumatology response rates were similar following treatment with either CH-1504 or MTX. Furthermore, Chelsea Therapeutics are developing the L-isomer of CH-1504, CH-4051, which displays improved in vitro potency over with racemate and appears to be Chelsea Therapeutics' preferred candidate for future development. Inert antifolates appear to be a promising drug class for the treatment of RA because the disease-modifying properties of MTX are retained, but the therapeutic window of the inert antifolates is improved. However, further trials are required to establish the efficacy and long-term safety in a wider population of patients with RA.
