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

https://doi.org/10.1016/j.bmcl.2008.06.052Get rights and content

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 t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.

Section snippets

Acknowledgments

The authors thank Partners Healthcare for financial support. This work was also supported in part by NIH Grants HL079943 (P.B.Y.), HL074352 (K.D.B.), and HL079267 (R.T.P.), the Harvard NeuroDiscovery Center (G.D.C., X.X. and J.K.L.), a Pulmonary Hypertension Association Mentored Clinical Scientist Award (P.B.Y.) and a grant from the GlaxoSmithKline Research & Education Foundation for Cardiovascular Disease (P.B.Y.). The pharmacokinetic study was performed by Absorption Systems (Exton, PA) and

References and notes (26)

  • O. Eickelberg et al.

    Trends Cardiovasc. Med.

    (2007)
    P.B. Yu et al.

    J Biol. Chem.

    (2005)
  • D. Liu et al.

    Blood

    (2007)
  • L. Ye et al.

    Histol. Histopathol.

    (2007)
  • I.Y. Kim et al.

    Clin. Cancer Res.

    (2003)
  • P.C. Billings et al.

    J. Bone Miner Res.

    (2008)
    E.M. Shore et al.

    Nat. Genet.

    (2006)
  • I. Kondolff et al.

    Synlett

    (2005)
  • C. Legault et al.

    J. Org. Chem.

    (2003)
  • Y. Tamaru et al.

    J. Chem. Soc., Perkin Trans. 1

    (1975)
  • J.S. Sawyer et al.

    Bioorg. Med. Chem. Lett.

    (2004)
    F. Gellibert et al.

    J. Med. Chem.

    (2004)
  • D. Chen et al.

    Growth Factors

    (2004)
    A. Zwijsen et al.

    FEBS Lett.

    (2003)
    A. Nohe et al.

    Cell Signal

    (2004)
  • P.B. Yu et al.

    Nat. Chem. Biol.

    (2008)
    J.L. Babitt et al.

    J. Clin. Invest.

    (2007)
    G. Weiss et al.

    N. Engl. J. Med.

    (2005)
  • E. Gazzerro et al.

    Curr. Opin. Pharmacol.

    (2007)
  • Cited by (291)

    View all citing articles on Scopus
    View full text