1HY7

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

Summary for 1HY7

• Entry DOI: 10.2210/pdb1hy7/pdb
• Related: 1CQR 1D5J 1D7X 1D8F 1D8M 1G49
• Descriptor: STROMELYSIN-1, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: mixed alpha beta structure, zinc protease, inhibited, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P08254
• Total number of polymer chains: 2
• Total formula weight: 39738.61

Authors

Natchus, M.G.,Bookland, R.G.,Laufersweiler, M.J.,Pikul, S.,Almstead, N.G.,De, B.,Janusz, M.J.,Hsieh, L.C.,Gu, F.,Pokross, M.E.,Patel, V.S.,Garver, S.M.,Peng, S.X.,Branch, T.M.,King, S.L.,Baker, T.R.,Foltz, D.J.,Mieling, G.E. (deposition date: 2001-01-18, release date: 2002-01-18, Last modification date: 2024-02-07)

Primary citation

Natchus, M.G.,Bookland, R.G.,Laufersweiler, M.J.,Pikul, S.,Almstead, N.G.,De, B.,Janusz, M.J.,Hsieh, L.C.,Gu, F.,Pokross, M.E.,Patel, V.S.,Garver, S.M.,Peng, S.X.,Branch, T.M.,King, S.L.,Baker, T.R.,Foltz, D.J.,Mieling, G.E.
Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.
J.Med.Chem., 44:1060-1071, 2001

PubMed Abstract: A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.

PubMed: 11297453
DOI: 10.1021/jm000477l

Experimental method

X-RAY DIFFRACTION (1.5 Å)