The discovery and optimization of a series of heterocyclic non-peptide matrix metalloproteinase inhibitors derived from a 6H-1,3,4-thiadiazine scaffold is described. 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 produced the selective inhibitor (2R)-N-[5-(4-bromophenyl)-6H-1,3,4-thiadiazine-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-thiadiazine-2-amine hydrobromide gave detailed design information on binding interactions for thiadiazine-based MMP inhibitors.