1hy7 Citations

Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.

Abstract

A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.

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  1. Future challenges facing the development of specific active-site-directed synthetic inhibitors of MMPs. Cuniasse P, Devel L, Makaritis A, Beau F, Georgiadis D, Matziari M, Yiotakis A, Dive V. Biochimie 87 393-402 (2005)
  2. Targeting matrix metalloproteases to improve cutaneous wound healing. Xue M, Le NT, Jackson CJ. Expert Opin Ther Targets 10 143-155 (2006)
  3. Matrix metalloproteinase inhibitors: do they have a place in anticancer therapy? Rudek MA, Venitz J, Figg WD. Pharmacotherapy 22 705-720 (2002)
  4. Synthetic applications of aliphatic unsaturated alpha-H-alpha-amino acids. Kaiser J, Kinderman SS, van Esseveldt BC, van Delft FL, Schoemaker HE, Blaauw RH, Rutjes FP. Org Biomol Chem 3 3435-3467 (2005)
  5. Arylsulfonamides and selectivity of matrix metalloproteinase-2: An overview. Adhikari N, Mukherjee A, Saha A, Jha T. Eur J Med Chem 129 72-109 (2017)

Articles citing this publication (21)