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Chemical Structure| 658084-64-1 Chemical Structure| 658084-64-1

Structure of (E)-Daporinad
CAS No.: 658084-64-1

Chemical Structure| 658084-64-1

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(E)-Daporinad (FK866) demonstrates remarkable effectiveness as an inhibitor of nicotinamide phosphoribosyltransferase (NMPRTase; Nampt), boasting an IC50 of 0.09 nM.

Synonyms: APO866; FK866; K 22.175

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Jooman Park ; Ruoci Hu ; Yanyu Qian ; Shaolei Xiong ; Asma Sana El-Sabbagh ; Meram Ibrahim , et al.

Abstract: Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving tolerance in mice. Mechanistically, we found that phosphoribosyl (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.

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Park, Jooman ; Hu, Ruoci ; Xiong, Shaolei ; Qian, Yanyu ; El-Sabbagh, Asma Sana ; Ibrahim, Meram , et al.

Abstract: Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. Highlights: Estrogen restores beige adipocyte failure along with improved energy metabolism in old mice.Estrogen enhances the thermogenic gene program by mitigating age-induced ER stress.Estrogen enhances the beige adipogenesis derived from SMA+ APCs.Inhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis.

Keywords: Aging ; Beige adipocyte formation ; Estrogen ; ER stress ; NAMPT

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Alternative Products

Product Details of (E)-Daporinad

CAS No. :658084-64-1
Formula : C24H29N3O2
M.W : 391.51
SMILES Code : O=C(NCCCCC1CCN(C(C2=CC=CC=C2)=O)CC1)/C=C/C3=CC=CN=C3
Synonyms :
APO866; FK866; K 22.175
MDL No. :MFCD10565943
InChI Key :KPBNHDGDUADAGP-VAWYXSNFSA-N
Pubchem ID :6914657

Safety of (E)-Daporinad

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Isoform Comparison

Biological Activity

Target
  • Transferase

    NMPRTase, Ki:0.4 nM

In Vitro:

Cell Line
Concentration Treated Time Description References
mouse embryo fibroblasts (MEFs) 10 nM FK866 significantly modifies the circadian expression of Per2 and Dbp, causing an earlier onset of the circadian peak for both genes by 3–4 hours and increasing the amplitude of oscillation by 30–40%. PMC6501775
neonatal rat cardiomyocytes (NRC) 10 μM 72 hours To evaluate the effect of FK866 on NAD+ levels, results showed that FK866 significantly reduced intracellular NAD+ levels, but NR fully restored NAD+ levels. PMC6954688
neonatal rat cardiomyocytes (NRC) 1 μM 24 hours To evaluate the effect of NR on NAD+ levels, results showed that NR significantly increased intracellular NAD+ levels. PMC6954688
RAW 264.7 cells 200 nM overnight To investigate the effect of FK866 on inflaμMatory responses, results showed that FK866 significantly reduced the release of proinflaμMatory cytokines in LPS-stimulated RAW 264.7 cells. PMC6145287
MODE-K cells 200 nM overnight To investigate the effect of FK866 on inflaμMatory responses, results showed that FK866 did not significantly affect the expression of PARP1 and Sirt6 in flagellin-stimulated MODE-K cells. PMC6145287
SCG neurites 100 nM 1 day To test the protective effect of FK866 on neurite injury, the results showed that FK866 significantly promoted neurite survival. PMC4392071
DRG neurites 100 nM 1 day The FK866 experiment was repeated in DRG neurites, and the results showed that FK866 also promoted neurite survival. PMC4392071

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
mice mouse model of dilated cardiomyopathy (DCM) oral 40 mM starting at the age of 8 weeks and lasting for 3 months To evaluate the protective effect of NR on cardiac function, results showed that NR significantly protected cardiac function and prevented cardiac dilatation and thinning. PMC6954688
mice DSS-induced colitis model intraperitoneal injection 30 mg/kg once daily for 30 days To investigate the effect of FK866 on DSS-induced colitis, results showed that FK866 significantly ameliorated the clinical symptoms of colitis, reduced inflammation, and suppressed tumorigenesis. PMC6145287
mice experimental OA model intraperitoneal injection 30 mg/kg Daily for 8 weeks FK866 significantly inhibited cartilage destruction induced by DMM surgery PMC4345811
Mice Hepatic ischemia-reperfusion injury model Intraperitoneal injection 25 mg/kg Twice a week for 6 weeks FK866 inhibition of the NAMPT-mediated NAD salvage pathway exacerbated hepatic ischemia-reperfusion injury, leading to increased mortality, severe liver lesions, elevated serum ALT and AST levels, increased necrotic areas, and enhanced inflammatory responses in mice. PMC9762284
Zebrafish Zebrafish larvae 15 mg/kg daily for 21 days To test the protective effect of FK866 on neurite injury in zebrafish larvae, the results showed that FK866 significantly delayed neurite degeneration. PMC4392071

Clinical Trial:

NCT Number Conditions Phases Recruitment Completion Date Locations
NCT00432107 Melanoma PHASE2 COMPLETED 2025-03-09 Department of Dermatology, Med... More >>ical University Graz, Graz, 8036, Austria|Department of Dermatology, Hopital Henri Modor, Créteil, 94010, France|Department of Dermatologie, Hotel Dieu, Nantes, 44093, France|Department of Dermatology, Charité University Hospital Berlin, Berlin, 10117, Germany|University Clinic for Dermatology, Medical Faculty of Mannheim of the Heidelberg University, Mannheim, 68167, Germany|Department of Dermatology, University Hospital of Zürich, Zürich, 8091, Switzerland Less <<
NCT00435084 B-cell Chronic Lymphocytic Leu... More >>kemia Less << PHASE1|PHASE2 COMPLETED 2025-04-09 Department of Heamtology, Card... More >>iff and Vale NHS Trust, Cardiff, CF14 4 WX, United Kingdom|Department of Heamtology, Leeds General Infirmary, Leeds, LS1 3EX, United Kingdom|Department of Heamtology, Bart's and the London NHS Trust, London, EC1A 7BE, United Kingdom|Department of Heamtology, University Hospital of NHS Trust, Nottingham, NG5 1PB, United Kingdom Less <<
NCT00431912 Cutaneous T-cell Lymphoma PHASE2 COMPLETED 2025-09-11 Department of Dermatology, Med... More >>ical University Graz, Graz, 8036, Austria|Deapartment of Dermatology, Créteil, 94010, France|department of Dermatologie, Hotel Dieu, Nantes, 44093, France|University Clinic for Dermatology, Medical Faculty of Mannheim of the Heidelberg University, Mannheim, 68167, Germany|Department of Dermatology, University Hospital of Zürich, Zürich, 8091, Switzerland Less <<

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.55mL

0.51mL

0.26mL

12.77mL

2.55mL

1.28mL

25.54mL

5.11mL

2.55mL

References

 

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