Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase

J Med Chem. 2006 Aug 10;49(16):5018-22. doi: 10.1021/jm060479r.

Abstract

Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide (MAD) have been prepared as potential inhibitors of IMP dehydrogenase. A coupling of the mycophenolic (hydroxymethyl)phosphonate 6 with the phosphitylated adenosine analogue 11 followed by oxidation and deprotection afforded the phosphophosphonate 8. A similar coupling between adenosine (hydroxymethyl)phosphonate 10 and phosphitylated mycophenolic alcohol 5 gave the corresponding phosphophosphonate 13. Both 8 and 13 (Ki = 20-87 nM) were found to be the most potent cofactor type inhibitors of IMP dehydrogenase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine Nucleotides / chemical synthesis*
  • Adenine Nucleotides / chemistry
  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / chemical synthesis
  • Adenosine Monophosphate / chemistry
  • Humans
  • IMP Dehydrogenase / antagonists & inhibitors*
  • IMP Dehydrogenase / chemistry*
  • Mycophenolic Acid / analogs & derivatives*
  • Mycophenolic Acid / chemical synthesis
  • Mycophenolic Acid / chemistry
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Structure-Activity Relationship

Substances

  • Adenine Nucleotides
  • Organophosphonates
  • P(1)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)methylenephospho-P(2)-(adenosin-5'-yl)phosphonate
  • P(1)-(adenosin-5'-yl)methylenephospho-P(2)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)phosphonate
  • mycophenolic adenine dinucleotide
  • Adenosine Monophosphate
  • IMP Dehydrogenase
  • Mycophenolic Acid