Kathleen M. Donahue

Inhibitors of MMP-1: an examination of P1′ Cα gem-disubstitution in the succinamide hydroxamate series

Abstract The effect of P 1 ′ C α gem-disubstitution in a series of succinamide hydroxamate inhibitors of MMP-1 has been investigated. While in all cases P 1 ′ gem-disubstitution led to loss of potency relative to the corresponding P 1 ′ isobutyl and phenyl compounds 1 and 3 , respectively, the loss of activity was less pronounced in certain instances, e.g., the P 1 ′ gem-cyclohexyl analogue 12 IC 50 = 0.15 μM).

Inhibitors of MMP-1: an examination of P1′ Cα gem-disubstitution in the N-carboxyalkylamine and glutaramide carboxylate series

Abstract Modification of the N-carboxyalkylamine 3 by independent replacement of the P1′ NH group for CH2 and introduction of P1′ gem-cyclohexyl substitution affords compounds 5 and 6a which retain appreciable activity against MMP-1 (IC50s = 0.023 μM and 0.09 μM, respectively). The glutaramide 7a which incorporates both these structural changes also retains potent activity (IC50 = 0.038 μM).

A novel rearrangement forming 4,5,6,11-tetra-hydrobenzo[6,7]cycloocta[1,2-b]thiophen-6,11-imines

Exposure of the spirocyclic isoindolines 9 and 16 and the spirocyclic ether 23 to HBr gas in methylene chloride at 0°C leads to the formation of the bridged heterocycles 10, 17, and 24 respectively. These novel rearrangements probably occur via retro-Mannich fragmentation and subsequent intramolecular Mannich reaction on the thiophene ring.