Structure-activity Relationship Study of Bone Morphogenetic Protein (BMP) Signaling Inhibitors

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2008 Jul 16

PMID 18621530

Citations 195

Authors

Gregory D Cuny

Paul B Yu

Joydev K Laha

Xuechao Xing

Ji-Feng Liu

Carol S Lai

Donna Y Deng

Chetana Sachidanandan

Kenneth D Bloch

Randall T Peterson

Affiliations

Soon will be listed here.

Abstract

A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.

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References

Yu P, Hong C, Sachidanandan C, Babitt J, Deng D, Hoyng S . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007; 4(1):33-41. PMC: 2727650. DOI: 10.1038/nchembio.2007.54. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Lober S, Hubner H, Utz W, Gmeiner P . Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). J Med Chem. 2001; 44(17):2691-4. DOI: 10.1021/jm015522j. View

Wu Z, Fraley M, Bilodeau M, Kaufman M, Tasber E, Balitza A . Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR. Bioorg Med Chem Lett. 2004; 14(4):909-12. DOI: 10.1016/j.bmcl.2003.12.007. View

Ye L, Lewis-Russell J, Kyanaston H, Jiang W . Bone morphogenetic proteins and their receptor signaling in prostate cancer. Histol Histopathol. 2007; 22(10):1129-47. DOI: 10.14670/HH-22.1129. View

Whitty A, Kumaravel G . Between a rock and a hard place?. Nat Chem Biol. 2006; 2(3):112-8. DOI: 10.1038/nchembio0306-112. View

Nohe A, Keating E, Knaus P, Petersen N . Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2003; 16(3):291-9. DOI: 10.1016/j.cellsig.2003.08.011. View

Shore E, Xu M, Feldman G, Fenstermacher D, Cho T, Choi I . A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006; 38(5):525-7. DOI: 10.1038/ng1783. View

Yu P, Beppu H, Kawai N, Li E, Bloch K . Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligand-specific gain of signaling in pulmonary artery smooth muscle cells. J Biol Chem. 2005; 280(26):24443-50. DOI: 10.1074/jbc.M502825200. View

10.

Fraley M, Rubino R, Hoffman W, Hambaugh S, Arrington K, Hungate R . Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics. Bioorg Med Chem Lett. 2002; 12(24):3537-41. DOI: 10.1016/s0960-894x(02)00827-2. View

11.

Eickelberg O, Morty R . Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: remodeling revisited. Trends Cardiovasc Med. 2007; 17(8):263-9. DOI: 10.1016/j.tcm.2007.09.003. View

12.

Baudoin O . New approaches for decarboxylative biaryl coupling. Angew Chem Int Ed Engl. 2007; 46(9):1373-5. DOI: 10.1002/anie.200604494. View

13.

Callahan J, Burgess J, Fornwald J, Gaster L, Harling J, Harrington F . Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem. 2002; 45(5):999-1001. DOI: 10.1021/jm010493y. View

14.

Sawyer J, Beight D, Britt K, Anderson B, Campbell R, Goodson Jr T . Synthesis and activity of new aryl- and heteroaryl-substituted 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. Bioorg Med Chem Lett. 2004; 14(13):3581-4. DOI: 10.1016/j.bmcl.2004.04.007. View

15.

Chen D, Zhao M, Mundy G . Bone morphogenetic proteins. Growth Factors. 2004; 22(4):233-41. DOI: 10.1080/08977190412331279890. View

16.

Fraley M, Hoffman W, Rubino R, Hungate R, Tebben A, Rutledge R . Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors. Bioorg Med Chem Lett. 2002; 12(19):2767-70. DOI: 10.1016/s0960-894x(02)00525-5. View

17.

Takata M, Filippov G, Liu H, Ichinose F, Janssens S, Bloch D . Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent and NO-independent mechanisms. Am J Physiol Lung Cell Mol Physiol. 2001; 280(2):L272-8. DOI: 10.1152/ajplung.2001.280.2.L272. View

18.

Gellibert F, Woolven J, Fouchet M, Mathews N, Goodland H, Lovegrove V . Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-beta type I receptor inhibitors. J Med Chem. 2004; 47(18):4494-506. DOI: 10.1021/jm0400247. View

19.

Weiss G, Goodnough L . Anemia of chronic disease. N Engl J Med. 2005; 352(10):1011-23. DOI: 10.1056/NEJMra041809. View

20.

Babitt J, Huang F, Xia Y, Sidis Y, Andrews N, Lin H . Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007; 117(7):1933-9. PMC: 1904317. DOI: 10.1172/JCI31342. View