Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: design, synthesis and structure-activity relationship.
The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1' hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1' directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1' directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 A X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1' directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species.
Matter
Hans
H
Aventis Pharma Deutschland GmbH, D-65926 Frankfurt am Main, Germany. hans.matter@aventis.com
Schudok
Manfred
M
Schwab
Wilfried
W
Thorwart
Werner
W
Barbier
Denis
D
Billen
Günter
G
Haase
Burkhard
B
Neises
Bernhard
B
Weithmann
Klaus
K
Wollmann
Theo
T
D000818:Animals; D001682:Biological Availability; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D044005:Tetrahydroisoquinolines
D007202:Indicators and Reagents; D007546:Isoquinolines; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D044005:Tetrahydroisoquinolines; C031270:1,2,3,4-tetrahydroisoquinoline carboxylic acid