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.

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.

[1]  M. Fleming,et al.  Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. , 2011, Blood.

[2]  Tomokazu Fukuda,et al.  BMP type I receptor inhibition reduces heterotopic ossification , 2008, Nature Medicine.

[3]  C. Lindsley,et al.  Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines , 2008 .

[4]  D. Scadden,et al.  Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. , 2011, Blood.

[5]  Charles C Hong,et al.  Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. , 2008, Nature chemical biology.

[6]  E. Aikawa,et al.  Inhibition of Bone Morphogenetic Protein Signaling Reduces Vascular Calcification and Atherosclerosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[7]  R. Pignolo,et al.  A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton , 2007, Expert opinion on biological therapy.

[8]  C. Hong,et al.  Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. , 2011, Blood.

[9]  W. F. Hoffman,et al.  Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics. , 2002, Bioorganic & medicinal chemistry letters.

[10]  R. Derynck,et al.  SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS , 2005 .

[11]  C. Hong,et al.  Applications of small molecule BMP inhibitors in physiology and disease. , 2009, Cytokine & growth factor reviews.

[12]  In Ho Choi,et al.  A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva , 2006, Nature Genetics.

[13]  Randall T Peterson,et al.  Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[14]  W. R. Taylor,et al.  Pharmacological Suppression of Hepcidin Increases Macrophage Cholesterol Efflux and Reduces Foam Cell Formation and Atherosclerosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[15]  C. Lindsley,et al.  In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. , 2010, ACS chemical biology.

[16]  P. Hoen,et al.  BMP antagonists enhance myogenic differentiation and ameliorate the dystrophic phenotype in a DMD mouse model , 2011, Neurobiology of Disease.

[17]  Norio Miyaura,et al.  Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds , 1995 .