Third-generation immucillins: syntheses and bioactivities of acyclic immucillin inhibitors of human purine nucleoside phosphorylase

J Med Chem. 2009 Feb 26;52(4):1126-43. doi: 10.1021/jm801421q.

Abstract

ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alternatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of 1 and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K(d) = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Adenosine / analogs & derivatives
  • Catalytic Domain
  • Drug Design*
  • Humans
  • Molecular Conformation
  • Pliability
  • Protein Binding
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Pyrrolidines
  • Purine-Nucleoside Phosphorylase
  • Adenine
  • Adenosine
  • galidesivir