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

Darren W. Engers, Audrey Y. Frist, Craig W. Lindsley, Charles C. Hong, Corey R. Hopkins

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3248-3252
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number11
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

Keywords

  • ALK2 kinase
  • Bone morphogenic receptor (BMP)
  • ML347
  • Pyrazolo[15-a]pyrimidine
  • Selectivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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