Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors

Bioorg Med Chem. 2016 Dec 1;24(23):6149-6165. doi: 10.1016/j.bmc.2016.09.009. Epub 2016 Sep 14.

Abstract

Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1' binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.

Keywords: Fused pyrimidine-2-carboxamide; MMP-13; Matrix metalloproteinase; Osteoarthritis; Structure-based drug design; Zinc-binding group.

MeSH terms

  • ADAM17 Protein / antagonists & inhibitors
  • Amides / chemical synthesis
  • Amides / pharmacokinetics
  • Amides / pharmacology*
  • Animals
  • Drug Design
  • Humans
  • Matrix Metalloproteinase 13 / metabolism*
  • Matrix Metalloproteinase Inhibitors / chemical synthesis
  • Matrix Metalloproteinase Inhibitors / pharmacokinetics
  • Matrix Metalloproteinase Inhibitors / pharmacology*
  • Microsomes, Liver / metabolism
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Quinazolinones / chemical synthesis
  • Quinazolinones / pharmacokinetics
  • Quinazolinones / pharmacology*
  • Rats
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Zinc / chemistry*

Substances

  • 4-oxo-N-((4'-((((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)sulfonyl)methyl)biphenyl-3-yl)methyl)-3,4-dihydroquinazoline-2-carboxamide
  • Amides
  • Matrix Metalloproteinase Inhibitors
  • Pyrimidines
  • Quinazolinones
  • Triazoles
  • Matrix Metalloproteinase 13
  • ADAM17 Protein
  • ADAM17 protein, human
  • Zinc