subject: Study Of Tretinoin Metabolic Blocker [print this page] Tretinoin is an active metabolite of vitamin A. It plays an important role in cell proliferation, differentiation and apoptosis. There are many applications in the treatment of tumors and skin diseases. Tretinoin can promote immature cells during the develop process, such as the undifferentiated blood cells, nerves, skin and bone tissue stem cells differentiate into mature cells with special functions. It has an important role in the prevention of tumors, inducing tumor cell differentiation and apoptosis. Tretinoin has become the first drug for remission induction therapy and therefore it is considered to be the model of differentiation therapy induction.
ATRA mainly metabolic reacts with CYPs in the body. It makes 4 cyclohexene ring hydroxylation, generating 4 hydroxy ATRA, and then generate 4 oxo-reductase of ATRA, and then through the CYPs a series of metabolic processes to generate more polar metabolites excreted, thus losing their physiological activity. In rodent and human liver microsomes, the metabolic pathways of the AT-RA is the same, CYP2C8, CYP3A4 and CYP2C9 are involved in the metabolism of ATRA, but their lack of specificity to ATRA metabolism. Thus, the CYP26 inhibitor, blocked the rapid metabolism of retinoic acid in the body can play a role in inducing tumor cell differentiation and inhibition of tumor cell proliferation.
The main clinical application is limited due to the rapid metabolism of retinoic acid, many scientists into the development of retinoic acid metabolism blocking agents and minoxidil. Early retinoic acid metabolism blocking agents include: ketoconazole, miconazole, g enzymeyl metyrapone, fluconazole and the iraqi itraconazole. However, the inhibitory effect of these compounds is not obvious.
The discovery of ketoconazole for prostate cancer have a greater side effects, so need to find more to strengthen the efficiency and low toxicity of CYP26 inhibitors. Lia azole was found in the study of structure-activity relationship of imidazole derivatives. It can increase the concentration of ATRA in plasma. Human prostate cancer cells, breast cancer MCF27 cells, showed strong antiproliferative activity. Lia azoles CYP17, CYP19 and CYP26 have inhibited the lack of specificity, leading to side effects in clinical applications, and thus terminated the clinical study.
The design ideas of such compounds, naphthalene nucleus two imidazolyl propylamine side chain connections R116010, 6 analog ATRA carboxylic acid substituent. From the structure of the naphthalene core nucleus is equivalent to ATRA conjugate four-ene structure. Such compounds have a strong activity and the role of selective cis configuration of the two side-chain chiral carbon, and its activity than the strong trans-6 homologue activity of propionic acid naphthol ether better. Among the cosmetics material, compound shows good pharmacokinetic and biochemical characteristics, bioavailability of 99% on CYP26 showed a high degree of selectivity, the weak inhibition of CYP3A4, of CYP1A2, CYP2D6 and CYP2C9.
Retinoic acid metabolic blocker which uses CYP26 as a target has opened a new window for the treatment of tumors and skin diseases. It has been mad initial progress against the target of drug design and synthesis in recent years. And it designs many compounds with new structures. So far the research is very limited and only a few compounds enter into the clinical research. There are still many problems need to be solved. Thus finding more efficient and highly selective RAMBAs have great significance. So that they can be successfully used in the treatment of tumors and skin diseases.
