Design and synthesis of phosphinamide-based hydroxamic acids as inhibitors of matrix metalloproteinases.
A new series of hydroxamic acid-based matrix metalloproteinase (MMP) inhibitors containing a unique phosphinamide motif derived from D-amino acid was designed, synthesized, and tested for enzyme inhibition. Compounds with an R configuration at phosphorus were found to be potent MMP inhibitors while molecules with the S configuration were almost inactive. Structure-activity relationship studies of the series led to the discovery of the potent inhibitor 16 with IC50 = 20.5 nM and 24.4 nM against fibroblast collagenase (MMP-1) and stromelysin (MMP-3), respectively. The binding mode of this novel phosphinamide-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 16.
Pikul
S
S
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
McDow Dunham
K L
KL
Almstead
N G
NG
De
B
B
Natchus
M G
MG
Anastasio
M V
MV
McPhail
S J
SJ
Snider
C E
CE
Taiwo
Y O
YO
Chen
L
L
Dunaway
C M
CM
Gu
F
F
Mieling
G E
GE
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C116989:N-hydroxy-2-((methylphenylphosphinyl)benzylamino)-4-methylpentanamide; D009943:Organophosphorus Compounds; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1