title: Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors.
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.
authors.affiliation: 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
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yu
authors.forename: Joydev K
authors.initials: JK
authors.lastname: Laha
authors.forename: Xuechao
authors.initials: X
authors.lastname: Xing
authors.forename: Ji-Feng
authors.initials: JF
authors.lastname: Liu
authors.forename: Carol S
authors.initials: CS
authors.lastname: Lai
authors.forename: Donna Y
authors.initials: DY
authors.lastname: Deng
authors.forename: Chetana
authors.initials: C
authors.lastname: Sachidanandan
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000037:antagonists & inhibitors*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D005260:Female; D008297:Male; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D019485:Bone Morphogenetic Proteins; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D052004:Bone Morphogenetic Protein Receptors