RRC ID 41581
Author Fujisawa T, Igeta K, Odake S, Morita Y, Yasuda J, Morikawa T.
Title Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model.
Journal 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).
Volume 10(8)
Pages 2569-81
Published 2002-8
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 2.881
Times Cited 21
Human and Animal Cells