LDN-193189 Chemical Properties

Density 

1.33

storage temp. 

Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

solubility 

H2O: soluble5mg/mL, clear (warmed)

form 

powder

pka

8.79±0.10(Predicted)

color 

yellow to orange

Water Solubility 

H2O: 5mg/mL, clear (warmed)

InChIKey

XHBVYDAKJHETMP-UHFFFAOYSA-N

Safety Information

WGK Germany 

3

HS Code 

29339900

LDN-193189 Usage And Synthesis

Description

Normal development and tissue repair are controlled in part by SMADs, a family of intracellular proteins that are activated by signaling via serine/threonine kinase receptors of the TGF-β superfamily. LDN-193189 inhibits SMAD1/5/8 phosphorylation by the bone morphogenetic protein (BMP) type I receptors, which are known as activin receptor-like kinases (ALKs), with an IC₅₀ value of 4.9 nM. In in vitro kinase assays, it shows specificity for ALK1, 2, 3, and 6 (IC₅₀s = 0.8, 0.8, 5.3, and 16.7 nM, respectively) over ALK4 and 5 (IC₅₀s = 101 and 350 nM, respectively). LDN-193189 has been used to inhibit BMP type I receptor activity to study the pathogenesis of fibrodysplasia ossificans progressive, a congenital hyperossification disorder, and to examine the role of osteogenesis in prostate tumor metastases in bone.

Uses

4-(6-(4-(Piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinoline, is a selective inhibitor of bone morphogenetic protein (BMP) pathway, useful in the treatment of diseases. Potent BMP Inhibitor?, Promotes hPSC Neural Induction?.

Definition

ChEBI: 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline is a member of pyrimidines.

Biochem/physiol Actions

Although LDN193189 is a structural analog of dorsomorphin, these two drugs are found to establish different cellular responses. In vitro analysis reveals that LDN193189 inhibits a number of intracellular kinases such as, mitogen activated protein kinase 14 and 8 ( p38and c-Jun N-terminal kinase respectively), as well as those associated with AKT (serine/threonine kinase) and mTOR (mammalian target of rapamycin) signaling mechanisms. LDN193189 is known to elevate the levels hemoglobin and thus helps to prevent the onset of anemia of inflammation.

Synthesis

The general procedure for the synthesis of 4-(6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)quinolines, using the compound (CAS: 1062368-23-3) as starting material, was as follows: 5% Pd/C catalyst and intermediate 12 (20 mg, 0.37 mmol) were dissolved in a mixture of methanol (3 mL) and dichloromethane (2 mL) solvent for degassing. Subsequently, the reaction was carried out under hydrogen atmosphere for 4 hours at room temperature. Upon completion of the reaction, the reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to afford the target product 13 (13 mg, 86% yield). The product was characterized by 1H NMR (DMSO-d6) with the following chemical shifts: δ 9.75 (d, J = 2.2 Hz, 1H), 9.40 (br.s, 1H), 9.29 (d, J = 5.9 Hz, 1H), 9.28 (d, J = 2.2 Hz, 1H), 9.07 (s, 1H), 8.70 (d, J = 8.4 Hz, 1H), 8.70 (d, J = 8.4 Hz, 1H), and 8.51 (d, J = 5.9 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.21 (t, J = 7.6 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 3.51-3.58 (m, 4H). 3.20-3.30 (m, 4H).

References

[1] yu pb, deng dy, lai cs, hong cc, cuny gd, bouxsein ml, hong dw, mcmanus pm, katagiri t, sachidanandan c, kamiya n, fukuda t, mishina y, peterson rt, bloch kd. bmp type i receptor inhibition reduces heterotopic [corrected] ossification. nat med. 2008 dec;14(12):1363-9.
[2] boergermann jh1, kopf j, yu pb, knaus p. dorsomorphin and ldn-193189 inhibit bmp-mediated smad, p38 and akt signalling in c2c12 cells. int j biochem cell biol. 2010 nov;42(11):1802-7.
[3] helbing t1, herold em, hornstein a, wintrich s, heinke j, grundmann s, patterson c, bode c, moser m. inhibition of bmp activity protects epithelial barrier function in lung injury. j pathol. 2013 sep;231(1):105-16. doi: 10.1002/path.4215. epub 2013 jul 10.

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