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


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.




Copyright 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.