title: Design and synthesis of novel metalloproteinase inhibitors.
abstract: 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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. s.nakatani@ono.co.jp
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakatani
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikura
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nishita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itadani
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Sugiura
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohno
authors.forename: Kanji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: 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
chemical_list: 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