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.
authors: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Darren W
authors: DW
authors: Engers
authors: Audrey Y
authors: AY
authors: Frist
authors: Craig W
authors: CW
authors: Lindsley
authors: Charles C
authors: CC
authors: Hong
authors: Corey R
authors: CR
authors: Hopkins
mesh_terms: D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C583032:DMH1 compound; D006574:Heterocyclic Compounds, 2-Ring; C554430:LDN 193189; C584754:ML347; D020033:Protein Isoforms; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; C527752:pyrazolo(1,5-a)pyrimidine; C516138:dorsomorphin; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; D052004:Bone Morphogenetic Protein Receptors
references: Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):613-22
references: 22223731
references: BMC Cell Biol. 2007 Sep 19;8:41
references: 17880711
references: ACS Chem Biol. 2010 Feb 19;5(2):245-53
references: 20020776
references: Expert Opin Biol Ther. 2007 May;7(5):705-12
references: 17477807
references: Blood. 2011 Oct 13;118(15):4224-30
references: 21841161
references: Blood. 2011 Nov 3;118(18):4977-84
references: 21730356
references: Blood. 2011 May 5;117(18):4915-23
references: 21393479
references: Neurobiol Dis. 2011 Feb;41(2):353-60
references: 20940052
references: Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):409-18
references: 19914855
references: Annu Rev Cell Dev Biol. 2005;21:659-93
references: 16212511
references: Nat Chem Biol. 2008 Jan;4(1):33-41
references: 18026094
references: Cell Signal. 2011 Nov;23(11):1831-42
references: 21740966
references: Nat Genet. 2006 May;38(5):525-7
references: 16642017
references: Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):299-307
references: 22095982
references: Nat Med. 2008 Dec;14(12):1363-9
references: 19029982
references: Bioorg Med Chem Lett. 2002 Dec 16;12(24):3537-41
references: 12443771
references: Bioorg Med Chem Lett. 2008 Aug 1;18(15):4388-92
references: 18621530