title: New type of metalloproteinase inhibitor: design and synthesis of new phosphonamide-based hydroxamic acids.
abstract: A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar K(i) values against MMP-1, -3, -9, and TACE and also showed nanomolar IC(50) values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.
authors.affiliation: Department of Chemistry, R&D Laboratories, Nippon Organon K.K., 1-5-90, Tomobuchi-cho, Miyakojima-ku, Osaka 534-0016, Japan. masaaki-sawa@dainippon-pharm.co.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sawa
authors.forename: Takao
authors.initials: T
authors.lastname: Kiyoi
authors.forename: Kiriko
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kumihara
authors.forename: Minoru
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miyasaka
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ito
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hirayama
authors.forename: Tomomi
authors.initials: T
authors.lastname: Inoue
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kirii
authors.forename: Eiji
authors.initials: E
authors.lastname: Nishiwaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohmoto
authors.forename: Yu
authors.initials: Y
authors.lastname: Maeda
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ishibushi
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Yoshino
authors.forename: Hirosato
authors.initials: H
authors.lastname: Kondo
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1