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

40 Citations (Scopus)

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

Fingerprint

Bone Morphogenetic Protein Receptors
Molecular Probes
Structure-Activity Relationship
Scaffolds
Molecules
quinoline
pyrazolo(1,5-a)pyrimidine
LDN 193189
ML347
(6-(4-(2-piperidin-1-ylethoxy)phenyl))-3-pyridin-4-ylpyrazolo(1,5-a)pyrimidine
pyrimidine

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

Cite this

@article{27f910d278504cbc9bae6c52e9a3470a,
title = "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",
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.",
keywords = "ALK2 kinase, Bone morphogenic receptor (BMP), ML347, Pyrazolo[15-a]pyrimidine, Selectivity",
author = "Engers, {Darren W.} and Frist, {Audrey Y.} and Lindsley, {Craig W.} and Hong, {Charles C.} and Hopkins, {Corey R.}",
year = "2013",
month = "6",
day = "1",
doi = "10.1016/j.bmcl.2013.03.113",
language = "English (US)",
volume = "23",
pages = "3248--3252",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "11",

}

TY - JOUR

T1 - 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

T2 - The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe

AU - Engers, Darren W.

AU - Frist, Audrey Y.

AU - Lindsley, Craig W.

AU - Hong, Charles C.

AU - Hopkins, Corey R.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - 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.

AB - 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.

KW - ALK2 kinase

KW - Bone morphogenic receptor (BMP)

KW - ML347

KW - Pyrazolo[15-a]pyrimidine

KW - Selectivity

UR - http://www.scopus.com/inward/record.url?scp=84877578975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877578975&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2013.03.113

DO - 10.1016/j.bmcl.2013.03.113

M3 - Article

C2 - 23639540

AN - SCOPUS:84877578975

VL - 23

SP - 3248

EP - 3252

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 11

ER -