Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.
A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.
Cheng
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M
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
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B
B
Pikul
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Almstead
N G
NG
Natchus
M G
MG
Anastasio
M V
MV
McPhail
S J
SJ
Snider
C E
CE
Taiwo
Y O
YO
Chen
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Dunaway
C M
CM
Gu
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F
Dowty
M E
ME
Mieling
G E
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Janusz
M J
MJ
Wang-Weigand
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D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000187:drug effects; D002417:Cattle; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C404925:N-hydroxy-1-(4-methoxyphenyl)sulfonyl-4-benzyloxycarbonylpiperazine-2-carboxamide; D010879:Piperazines; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D013449:Sulfonamides; D008666:Metalloendopeptidases