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

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 (Ki = 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.