Structure-activity Relationship Study of Bone Morphogenetic Protein (BMP) Signaling Inhibitors

Bioorg Med Chem Lett. 2008 Aug 1;18(15):4388-92. doi: 10.1016/j.bmcl.2008.06.052. Epub 2008 Jun 27.

Abstract

A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.

Publication types

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

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors / antagonists & inhibitors*
  • Bone Morphogenetic Proteins / metabolism*
  • Combinatorial Chemistry Techniques
  • Female
  • Male
  • Mice
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Signal Transduction*
  • Structure-Activity Relationship

Substances

  • Bone Morphogenetic Proteins
  • Piperazines
  • Pyrazoles
  • Pyrimidines
  • dorsomorphin
  • Bone Morphogenetic Protein Receptors