Scope of the problem:
The dihydrofolate reductase (DHFR) is an enzyme which reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as the electron donor (reduced form of nicotinamide adenine dinucleotide phosphate). Tetrahydrofolic acid is used for the de novo synthesis of purines, thymidylic acid, and certain amino acids. Because tetrahydrofolic acid is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. However, as folate is needed by rapidly dividing cells to make thymine, this effect may be therapeutic.
Particularly, these inhibitors can be used as antiproliferative agent due to its inhibitory effect of cell divisions, such as for example in cancer chemotherapy because they can prevent cancer cells from dividing, and also in the treatment of other psoriasis, rheumatoid arthritis, inflammatory diseases of the digestive tract because they can also prevent normal cells from dividing.
Methotrexate and Pemetrexed are well known examples of antimetabolites of the antifolate type which competitively inhibits DHFR, however, serious adverse effects have been reported for these active ingredients. Therefore, from what is known in the art it is derived that there is still the need of providing an inhibitor of the DHFR in which the side effects are reduced.<br>
Our innovation:
-New class of DHFR inhibitors, in particular, photoisomerizable derivatives of a folate antimetabolite such as methotrexate and pemetrexed.
-Compositions containing them in a therapeutically effective amount with one or more pharmaceutically acceptable excipients or carriers
-Processes for their preparation and their uses in therapy
Competitive advantages: the active derivative compounds maintain the same desirable biological effect as do the reference active ingredient, with high activity and low side effects. The active moiety allows having a regioisomeric geometry Z/E that changes from one isomer to the active isomer upon exposure to light at a specific wavelength.
To be determined during further development
Patient need addressed: Any disease or condition mediated by DHFR (cancer, psoriasis, rheumatoid arthritis, inflammatory diseases)
Aida Castellanos Paez
