Design and synthesis of carboxylate inhibitors for matrix metalloproteinases.
A series of carboxylate compounds were prepared from N(alpha)-substituted 2,3-diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three-dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c,d, 22) and sulfonamide compounds (14b,c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10(-6) M order), depending on the substituent at the N(alpha)-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3-P1' compound 10b.
Fujisawa
T
T
Research Institute, Fuji Chemical Industries, Ltd., Takaoka, Toyama, Japan. morikawa@fuji-chemi.co.jp
Katakura
S
S
Odake
S
S
Morita
Y
Y
Yasuda
J
J
Yasumatsu
I
I
Morikawa
T
T
D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism
D002264:Carboxylic Acids; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D015032:Zinc