Details

Autor(en) / Beteiligte

• Schröder, Jörg
• Henke, Andreas
• Wenzel, Herbert
• Brandstetter, Hans
• Stammler, Hans G
• Stammler, Anja
• Pfeiffer, Wolf D
• Tschesche, Harald

Titel

Structure-Based Design and Synthesis of Potent Matrix Metalloproteinase Inhibitors Derived from a 6H-1,3,4-Thiadiazine Scaffold

Ist Teil von

• Journal of medicinal chemistry, 2001-09, Vol.44 (20), p.3231-3243

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2001

Quelle

MEDLINE

Beschreibungen/Notizen

• We describe a new generation of heterocyclic nonpeptide matrix metalloproteinase (MMP) inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. A screening effort was utilized to identify some chiral 6-methyl-1,3,4-thiadiazines that are weak inhibitors of the catalytic domain of human neutrophil collagenase (cdMMP-8). Further optimization of the lead compounds revealed general design principles that involve the placement of a phenyl or thienyl group at position 5 of the thiadiazine ring, to improve unprimed side affinity; the incorporation of an amino group at position 2 of the thiadiazine ring as the chelating agent for the catalytic zinc; the placement of a N-sulfonamide-substituted amino acid residue at the amino group, to improve primed side affinity; and the attachment of diverse functional groups at position 4 or 5 of the phenyl or thienyl group at the unprimed side, to improve selectivity. The new compounds were assayed against eight different matrix metalloproteinases, MMP-1, cdMMP-2, cdMMP-8, MMP-9, cdMMP-12, cdMMP-13, cdMMP-14, and the ectodomain of MMP-14, respectively. A unique combination of the above-described modifications produced the selective inhibitor (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazin-2-yl]-2-[(phenylsulfonyl)amino]propanamide with high affinity for MMP-9 (K i = 40 nM). X-ray crystallographic data obtained for cdMMP-8 cocrystallized with N-allyl-5-(4-chlorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrobromide gave detailed design information on binding interactions for thiadiazine-based MMP inhibitors.