Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe.

Engers DW, Frist AY, Lindsley CW, Hong CC, Hopkins CR
Bioorg Med Chem Lett. 2013 23 (11): 3248-52

PMID: 23639540 · PMCID: PMC3677712 · DOI:10.1016/j.bmcl.2013.03.113

A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.

Copyright © 2013 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Activin Receptors, Type I Animals Bone Morphogenetic Protein Receptors Half-Life Heterocyclic Compounds, 2-Ring Humans Mice Protein Binding Protein Isoforms Pyrazoles Pyrimidines Quinolines Rats Structure-Activity Relationship

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