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.