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

dc.contributor.authorCuny, Gregory D.
dc.contributor.authorYu, Paul B.
dc.contributor.authorLaha, Joydev K.
dc.contributor.authorXing, Xuechao
dc.contributor.authorLiu, Ji-Feng
dc.contributor.authorLai, Carol S.
dc.contributor.authorDeng, Donna Y.
dc.contributor.authorSachidanandan, Chetana
dc.contributor.authorBloch, Kenneth D.
dc.contributor.authorPeterson, Randall T.
dc.description.abstractA 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.
dc.identifier.citationCopyright 2008 Bioorganic and Medicinal Chemistry Letters. This is a post-print version of a published paper that is available at: Recoomended citation: Cuny, Gregory D., B. Yu Paul, Joydev K. Laha, Xuechao Xing, Ji-Feng Liu, Carol S. Lai, Donna Y. Deng, Chetana Sachidanandan, Kenneth D. Bloch, and Randall T. Peterson. "Structure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors." Bioorganic & medicinal chemistry letters 18, no. 15 (2008): 4388-4392. doi:10.1016/j.bmcl.2008.06.052. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.
dc.publisherBioorganic and Medicinal Chemistry Letters
dc.titleStructure–activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors


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