Structure of (E)-Daporinad
CAS No.: 658084-64-1
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
(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 estrogen (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 glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (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 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. 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.
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Keywords: Aging ; Beige adipocyte formation ; Estrogen ; ER stress ; NAMPT
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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Target |
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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 << |
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 |
Tags: (E)-Daporinad | FK866 | APO866 | FK 866 | FK-866 | APO866 | APO 866 | APO-866 | NAMPT inhibitor | NAD+ biosynthesis | Nicotinamide phosphoribosyl transferase | pre-B cell-enhancing factor | Pre-B cell colony enhancing factor | 658084-64-1
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