Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold

Schröder J, Henke A, Wenzel H, Brandstetter H, Stammler H-G, Stammler A, Pfeiffer WD, Tschesche H (2001)
JOURNAL OF MEDICINAL CHEMISTRY 44(20): 3231-3243.

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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)a mino]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.
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Schröder J, Henke A, Wenzel H, et al. Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY. 2001;44(20):3231-3243.
Schröder, J., Henke, A., Wenzel, H., Brandstetter, H., Stammler, H. - G., Stammler, A., Pfeiffer, W. D., et al. (2001). Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY, 44(20), 3231-3243.
Schröder, J., Henke, A., Wenzel, H., Brandstetter, H., Stammler, H. - G., Stammler, A., Pfeiffer, W. D., and Tschesche, H. (2001). Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY 44, 3231-3243.
Schröder, J., et al., 2001. Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY, 44(20), p 3231-3243.
J. Schröder, et al., “Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold”, JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, 2001, pp. 3231-3243.
Schröder, J., Henke, A., Wenzel, H., Brandstetter, H., Stammler, H.-G., Stammler, A., Pfeiffer, W.D., Tschesche, H.: Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold. JOURNAL OF MEDICINAL CHEMISTRY. 44, 3231-3243 (2001).
Schröder, J., Henke, A, Wenzel, Herbert, Brandstetter, H, Stammler, Hans-Georg, Stammler, A, Pfeiffer, WD, and Tschesche, Harald. “Structure-based design and synthesis of potent matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold”. JOURNAL OF MEDICINAL CHEMISTRY 44.20 (2001): 3231-3243.
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