6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE Chemical Properties

Melting point:

>228°C(dec.)

Density 

1.25±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

solubility 

DMSO: >2mg/mL (warmed)

pka

8.53±0.10(Predicted)

form 

powder

color 

white to beige

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

InChI

InChI=1S/C24H25N5O/c1-2-12-28(13-3-1)14-15-30-22-6-4-19(5-7-22)21-16-26-24-23(17-27-29(24)18-21)20-8-10-25-11-9-20/h4-11,16-18H,1-3,12-15H2

InChIKey

XHBVYDAKJHETMP-UHFFFAOYSA-N

SMILES

C12=C(C3C=CN=CC=3)C=NN1C=C(C1=CC=C(OCCN3CCCCC3)C=C1)C=N2

Safety Information

Hazard Codes 

Xn

Risk Statements 

20/21/22

Safety Statements 

36/37

WGK Germany 

3

HS Code 

2933599590

6-[4-(2-PIPERIDIN-1-YLETHOXY)PHENYL]-3-PYRIDIN-4-YLPYRAZOLO[1,5-A]PYRIMIDINE Usage And Synthesis

Description

Dorsomorphin (866405-64-3) is a potent, selective and ATP-competitive inhibitor of AMP-activated protein kinase (AMPK) (Ki = 109 nM).1 It displays no significant inhibition of ZAPK, SYK, PKCT, PKA and JAK3. It inhibits bone morphogenetic protein (BMP) type I receptors (ALK2, ALK3 and ALK6).2 Dorsomorphin has been shown to promote cardiomyogenesis in mouse embryonic stem cells (ESCs) in vitro.3 Dorsomorphin also induces autophagy in cancer cell lines via a mechanism independent of AMPK inhibition.4

Uses

Dorsomorphin has been used:

• as an inhibitor of adenosine monophosphate-activated protein kinase (AMPK) to find the effects of trans-resveratrol on lipid mobilization in 3T3-L1 (a murine cell line of adipocytes) cells
• as an AMPK inhibitor, to indicate the involvement of AMPK/mTOR (mammalian target of rapamycin) pathway in LRG (liraglutide) -induced autophagy
• in the induction step, employed in in vitro differentiation of Friedreich′s ataxia (FRDA) and induced pluripotent stem cells (iPSCs) to neurospheres and neurons using ES (embryonic stem cell) media

Uses

A potent inhibitor of AMPK and fatty acid biosynthesis.

Definition

ChEBI: A pyrazolopyrimidine that is pyrazolo[1,5-a]pyrimidine which is substituted at positions 3 and 6 by pyridin-4-yl and p-[2-(piperidin-1-yl)ethoxy]phenyl groups, respectively. It is a potent, selective, reversible, and ATP-competiti e inhibitor of AMPK (AMP-activated protein kinase, EC 2.7.11.31) and a selective inhibitor of bone morphogenetic protein (BMP) signaling.

General Description

A cell-permeable pyrrazolopyrimidine compound that inhibits against KDR/VEGFR2, ALK2/BMPR-I, AMPK kinase activity (IC₅₀ = 25.1, 148, and 234.6 nM, respectively), while exhibiting much reduced or little effect toward ALK5/TGFβR-I, ZAPK, Syk, PKCθ, PKA, or JAK3. Shown to block both BMP pathway-dependent dorsoventral development (EC₁₀₀ = 2.5 μM) and VEGF signaling-dependent intersomitic vessel formation (EC₅₀ = 5 μM) in zebrafish embryo in vivo. Commonly used in combination with AMPK activators AICAR (Cat. No. 123040) and/or Metformin (Cat. No. 317240) for studying AMPK-dependent cellular events in vitro and physiological responses in animals in vivo.

Biological Activity

Potent and selective inhibitor of AMP-activated protein kinase (AMPK) (K i = 109 nM). Displays no significant activity on several structurally related kinases including ZAPK, SYK, PKC θ , PKA and JAK3. Inhibits AMPK activation induced by AICAR and metformin. Also inhibits bone morphogenic protein (BMP) type I receptors (ALK2, ALK3 and ALK6). Promotes cardiomyogenesis in mouse embryonic stem cells (ESCs) in vitro .

Biochem/physiol Actions

Target IC50: 25.1, 148, and 234.6 nM, against KDR/VEGFR2, ALK2/BMPR-I, AMPK kinase activity, respectively

Background

Dorsomorphin is a potent and reversible AMP-activated protein kinase inhibitor that competes with ATP in the absence of AMP with a Ki value of 109 nM. This small compound is selective, displaying no significant inhibition of other kinases inclusive of ZAPK, SYK, PKCθ, PKA, and JAK3. Research has shown that Dorsomorphin inhibits tumor cell proliferation and induces apoptosis through mechanisms independent of the AMPK pathway. This compound inhibits the effects that AICAR and metformin have on inactivating acetyl-CoA carboxylase and selectively inhibits the BMP type I receptors ALK2, ALK3, and ALK6.

References

[1] ZHOU G, MYERS R W, LI Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action.[J]. The Journal of clinical investigation, 2001, 1 1: 0. DOI:10.1172/jci13505
[2] PAUL B YU. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism[J]. Nature chemical biology, 2007, 4 1: 33-41. DOI:10.1038/nchembio.2007.54
[3] JIJUN HAO. Dorsomorphin, a selective small molecule inhibitor of BMP signaling, promotes cardiomyogenesis in embryonic stem cells.[J]. PLoS ONE, 2008, 3 8: e2904. DOI:10.1371/journal.pone.0002904
[4] LJUBICA VUCICEVIC. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway.[J]. Autophagy, 2011, 7 1: 40-50. DOI:10.4161/auto.7.1.13883

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