2. Academic Validation
  3. Design and synthesis of piperazine-based matrix metalloproteinase inhibitors

Design and synthesis of piperazine-based matrix metalloproteinase inhibitors

  • J Med Chem. 2000 Feb 10;43(3):369-80. doi: 10.1021/jm990366q.
M Cheng 1,  B De,  S Pikul,  N G Almstead,  M G Natchus,  M V Anastasio,  S J McPhail,  C E Snider,  Y O Taiwo,  L Chen,  C M Dunaway,  F Gu,  M E Dowty,  G E Mieling,  M J Janusz,  S Wang-Weigand
Affiliations

Affiliation

  • 1 Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
PMID: 10669564 DOI: 10.1021/jm990366q
Abstract

A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the Enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.

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