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.
Gregory D Cuny  1 ,  Paul B Yu ,  Joydev K Laha ,  Xuechao Xing ,  Ji-Feng Liu ,  Carol S Lai ,  Donna Y Deng ,  Chetana Sachidanandan ,  Kenneth D Bloch ,  Randall T Peterson
Affiliations
  • 1. Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA. [email protected]
PMID: 18621530 DOI: 10.1016/j.bmcl.2008.06.052
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.

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