Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors.
The synthesis and biological evaluation of orally active inhibitors of matrix metalloproteinase are reported. Modifications of the P2' position and the alpha-substituent of hydroxamic acid derivatives were carried out, and revealed that the P2' substituent influenced the MMP inhibitory activities in vitro and in plasma after oral administration. The hydroxamates with phenylglycine at the P2' position were absorbed well orally. Compound 15e, which exhibited the longest duration of inhibitory activity in plasma after oral administration among the phenylglycine derivatives (5a-5d, 15a, 15c, 15e), was evaluated in a rat adjuvant arthritis model. A reduction in hind foot pad swelling and improvements of some inflammatory parameters were demonstrated when the compound was administered orally. These results indicate the potential of MMP inhibitors for rheumatoid arthritis.
Hirayama
R
R
New Drug Discovery Research Laboratory, Osaka, Japan.
Yamamoto
M
M
Tsukida
T
T
Matsuo
K
K
Obata
Y
Y
Sakamoto
F
F
Ikeda
S
S
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001682:Biological Availability; D017364:Collagenases / Q000097:blood; D004195:Disease Models, Animal; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000097:blood; D006614:Hindlimb / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases