| Project/Area Number |
10470461
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Chemical pharmacy
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
HASHIMOTO Yuichi Institute of Molecular and Cellular Biosciences, The University of Tokyo, professor, 分子細胞生物学研究所, 教授 (90164798)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Hisayoshi Institute of Molecularand Cellular Biosciences, The University of Tokyo, assistant professor, 分子細胞生物学研究所, 助手 (80225531)
KOISO Yuikiko Institute of Molecularand Cellular Biosciences, The University of Tokyo, assistant professor, 分子細胞生物学研究所, 助手 (50092200)
森崎 尚子 東京大学, 分子細胞生物学研究所, 講師 (00092354)
白井 隆一 東京大学, 分子細胞生物学研究所, 助手 (80183838)
|
|---|
| Project Period (FY) |
1998 – 2001
|
| Project Status |
Completed (Fiscal Year 2001)
|
| Budget Amount *help |
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥4,300,000 (Direct Cost: ¥4,300,000)
|
|---|
| Keywords | nuclear receptor / retioids / thalidomide / androgen / structural development / molecular design / enzyme inhibitors / ligand / 構造活性相関 / ヘシン / アンドロジェン / アンタゴニスト / フタルイミド / ホモフタルイミド / シナージスト / 医薬品化学 / 阻害剤 / 情報伝達物質 |
|---|
| Research Abstract |
The full-scale commercial appearance of antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In this situation, biological response modifiers (BRM's), which are not based on selective toxicity, are expected to be useful. There exist several types of BRM's, including retinoids which act directly on cells at the gene expression level, and thalidomide (and related molecules) which modulate internal circumstances of our body. We have been engaged in medicinal chemical/structural development studies based on these bio-active compounds. Retinoids include all-tarans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bio-isosters, which elicit their biological effects by binding to their nuclear receptors, RAR's. ATRA has been used in differentiation therapy [typically for the treatment of acute promyelocytic leukemia (APL)] and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design has yielded class/subtype-selective agonists, synergists and antagonists of RAR's and their partner nuclear receptors, RXR's. Thalidomide elicits a wide range of pharmacological effects, including anti-cachexia, anti-angiogenic and antimetastatic activities. We have found that thalidomide is a multi-target drug. Hypothetical target events/molecules of thalidomide include TNF-alpha production, nuclear androgen receptor, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been : prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, anti-angiogenic agents, and anti-tumor promoting agents.
|
