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Bioorg Med Chem Lett. 2013 Jun 1;23(11):3248-52. doi: 10.1016/j.bmcl.2013.03.113. Epub 2013 Apr 11.

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.

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  • 1Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

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.

PMID:
23639540
[PubMed - indexed for MEDLINE]
PMCID:
PMC3677712
Free PMC Article

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