Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Activin Receptors, Type I / antagonists & inhibitors
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Activin Receptors, Type I / metabolism
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Animals
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Bone Morphogenetic Protein Receptors / antagonists & inhibitors*
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Bone Morphogenetic Protein Receptors / metabolism
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Half-Life
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Heterocyclic Compounds, 2-Ring / chemical synthesis*
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Heterocyclic Compounds, 2-Ring / chemistry
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Heterocyclic Compounds, 2-Ring / pharmacokinetics
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Humans
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Mice
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Protein Binding
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Pyrazoles / chemistry*
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Pyrazoles / metabolism
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Pyrazoles / pharmacokinetics
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / pharmacokinetics
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Quinolines / chemical synthesis*
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Quinolines / chemistry*
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Quinolines / metabolism
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Quinolines / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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DMH1 compound
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Heterocyclic Compounds, 2-Ring
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LDN 193189
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ML347
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Protein Isoforms
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Pyrazoles
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Pyrimidines
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Quinolines
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pyrazolo(1,5-a)pyrimidine
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dorsomorphin
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ACVR1 protein, human
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Activin Receptors, Type I
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Bone Morphogenetic Protein Receptors