|Budget Amount *help
¥8,100,000 (Direct Cost : ¥8,100,000)
Fiscal Year 2000 : ¥2,200,000 (Direct Cost : ¥2,200,000)
Fiscal Year 1999 : ¥2,700,000 (Direct Cost : ¥2,700,000)
Fiscal Year 1998 : ¥3,200,000 (Direct Cost : ¥3,200,000)
Retinoic acid acts as a specific modulator of cellular differentiation and proliferation. Its natural and synthetic analogs, classified as retinoids, have already proven their efficacy in the treatment of dermatological diseases as well as skin cancer and leukemia. In this project we have designed and synthesized several kinds of novel compounds which regulate the activities of retinoids.
Dibenzodiazepine derivatives exhibited unique retinoid-reguratory activity, depending on the substituents. LE135is RARβ (and α)-selective retinoid antagonist. On the other hand, HX600, which is a strtuctural isomer of LE135, exhibited retinoid synergistic activity. Mechanistic investigation showed that HX600 binds to RXR site of RXR-RAR heterodimers to synergize with RAR ligands. During the investigation on the structure-activity relationships of retinoid synergists, we found a nitrated anaolg of HX600, yielding HX531, is an RXR antagonist which can inhibit the differentiation-inducing activities of retinoids. Diphenylamine derivatives are another class of retinoid synergists. In this series, size and bulkiness of the N-alkyl group are significant for the activity. Among them, DA023 and DA124 exhibited higher synergistic potency than LGD1069, a typical RXR agonist.
Finally, we developed several thiazolidine derivatives with retinoid agonistic or synergistic activities. Some thiazolidinedione derivatives are known as the specific ligands for peroxisome proliferator-activated receptor γ (PPARγ). Compounds such as TZ191 and TZ335 are RXR agonists and exhibited potent retinoid synergistic activity in HL-60 assay.
The compounds described here regulate specifically the action of retinoids. Especially, since retinoid synergists can potenciate retinoidal action at low concentration, they may find application in the field of retinoid therapy. RXR ligand can modulate the action of other nuclear receptor ligands besides retinoids. Further investigations on their actions are in progress.