| RRC ID |
41581
|
| 著者 |
Fujisawa T, Igeta K, Odake S, Morita Y, Yasuda J, Morikawa T.
|
| タイトル |
Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model.
|
| ジャーナル |
Bioorg Med Chem
|
| Abstract |
A new series of succinate-based dual inhibitors against matrix metalloproteinases (MMPs) and tumor necrosis factor alpha converting enzyme (TACE) possessing highly-water solubility was designed, synthesized, and evaluated for enzyme inhibition. Incorporating of acidic or basic functional groups at the P(2)' position afforded sufficient water solubility without significant loss of inhibitory potencies. Compound 18e, which had a guanidino group at the P(2)' position as the basic functional group, exhibited broad inhibition against target enzymes for a relatively long period in rat plasma (beta t(1/2); 2.0h) after sc administration when compared with compounds possessing acidic functional groups (18a and 18b). Consequently, the representative compound 18e together with compound 18b, Marimastat and Trocade were evaluated in the rat adjuvant-induced arthritis model, a model of chronic cartilage destruction. It is concluded that the newly synthesized highly water-soluble compound 18e showed significant activity in suppressing hindpaw swelling and the bone destruction with a minimal administration period (days 3-7).
|
| 巻・号 |
10(8)
|
| ページ |
2569-81
|
| 公開日 |
2002-8-1
|
| DOI |
10.1016/s0968-0896(02)00109-8
|
| PII |
S0968089602001098
|
| PMID |
12057646
|
| MeSH |
ADAM Proteins
ADAM17 Protein
Amides
Animals
Arthritis / chemically induced
Arthritis / drug therapy*
Disease Models, Animal
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / pharmacology
Half-Life
Inflammation / drug therapy
Injections, Subcutaneous
Matrix Metalloproteinase Inhibitors*
Metalloendopeptidases / antagonists & inhibitors
Rats
Solubility
Succinic Acid / chemical synthesis
Succinic Acid / pharmacokinetics
Succinic Acid / pharmacology
|
| IF |
3.073
|
| 引用数 |
31
|
|
WOS 分野
|
CHEMISTRY, ORGANIC
CHEMISTRY, MEDICINAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
NB1RGB(RCB0222) |
