Highly water-soluble matrix metalloproteinases inhibitors and their effects in a rat adjuvant-induced arthritis model.
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).
Fujisawa
Tetsunori
T
Research Institute, Daiichi Fine Chemical Co., Ltd., 530 Chokeiji, Takaoka, Toyama 933-8511, Japan.
Igeta
Katsuhiro
K
Odake
Shinjiro
S
Morita
Yasuo
Y
Yasuda
Junko
J
Morikawa
Tadanori
T
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000577:Amides; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D007249:Inflammation / Q000188:drug therapy; D007279:Injections, Subcutaneous; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051381:Rats; D012995:Solubility; D019802:Succinic Acid / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000577:Amides; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019802:Succinic Acid; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat