New type of metalloproteinase inhibitor: design and synthesis of new phosphonamide-based hydroxamic acids.
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.
Sawa
Masaaki
M
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
Kiyoi
Takao
T
Kurokawa
Kiriko
K
Kumihara
Hiroshi
H
Yamamoto
Minoru
M
Miyasaka
Tomohiro
T
Ito
Yasuko
Y
Hirayama
Ryoichi
R
Inoue
Tomomi
T
Kirii
Yasuyuki
Y
Nishiwaki
Eiji
E
Ohmoto
Hiroshi
H
Maeda
Yu
Y
Ishibushi
Etsuko
E
Inoue
Yoshimasa
Y
Yoshino
Kohichiro
K
Kondo
Hirosato
H
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
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