Design and synthesis of novel metalloproteinase inhibitors.
A series of N-benzoyl 4-aminobutyric acid hydroxamate analogs were synthesized and evaluated as matrix metalloproteinase inhibitors. Synthetic work was focused on the chemical modification of the 4-aminobutyric acid part using easily available starting materials. As such, chemical modification was carried out using commercially available starting materials such as 4-aminobutyric acid, (+)- and (-)-malic acid, and D- and L-glutamic acid derivatives. Among the compounds tested, N-[4-(benzofuran-2-yl)benzoyl] 4-amino-4S-hydroxymethylbutyric acid hydroxamates derived from L-glutamic acid demonstrated more potent inhibitory activity against MMP-2 and MMP-9 compared with the corresponding 2S-hydroxy analogs or 3S-hydroxy analogs, respectively, which were derived from (-)-malic acid. Structure-activity relationship study is presented.
Nakatani
Shingo
S
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. s.nakatani@ono.co.jp
Ikura
Masahiro
M
Yamamoto
Shingo
S
Nishita
Yoshitaka
Y
Itadani
Satoshi
S
Habashita
Hiromu
H
Sugiura
Tsuneyuki
T
Ogawa
Koji
K
Ohno
Hiroyuki
H
Takahashi
Kanji
K
Nakai
Hisao
H
Toda
Masaaki
M
D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019714:Tissue Inhibitor of Metalloproteinases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D001572:Benzofurans; D002087:Butyrates; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C513538:N-(4-(benzofuran-2-yl)benzoyl)4-amino-4S-hydroxymethylbutyric acid; D019714:Tissue Inhibitor of Metalloproteinases