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

Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.

Author information

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. gcuny@rics.bwh.harvard.edu

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.

PMID:
18621530
PMCID:
PMC2570262
DOI:
10.1016/j.bmcl.2008.06.052
[Indexed for MEDLINE]
Free PMC Article

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