Design and synthesis of an orally active matrix metalloproteinase inhibitor.
A series of 4-(4-phenoxy)benzoylamino-4-methoxymethyloxymethyl butyric acid hydroxamates, which were derived from l-glutamic acid, were synthesized and evaluated as matrix metalloproteinase inhibitors. Most of the compounds listed in exhibited strong inhibitory activity against MMP-2 and MMP-9, as well as even stronger inhibitory activity against MMP-3, but showed relatively weak inhibition of MMP-1. Structure-activity relationships are discussed.
Yamamoto
Shingo
S
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Nakatani
Shingo
S
Ikura
Masahiro
M
Sugiura
Tsuneyuki
T
Nishita
Yoshitaka
Y
Itadani
Satoshi
S
Ogawa
Koji
K
Ohno
Hiroyuki
H
Takahashi
Kanji
K
Nakai
Hisao
H
Toda
Masaaki
M
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000737:chemistry; D006168:Guinea Pigs; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D018698:Glutamic Acid