GSK3335103
GSK3335103 is an orally active non-peptidic αvβ6 integrin inhibitor with a pIC50 of 8 and a pKi of 9.96. GSK3335103 blocks αvβ6 integrin-mediated cell adhesion and TGF-β1 activation, induces integrin internalization, recycling and lysosomal degradation, attenuates TGFβ signaling and reduces collagen deposition. GSK3335103 decreases the level of pSmad2 in BAL cells and collagen deposition in lung tissues in a mouse model of pulmonary fibrosis. GSK3335103 can be used in research related to pulmonary fibrosis.
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- CAS No.: 1893340-21-0
- 화학식: C27H36FN3O4
- 분자량:485.59
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보관:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Protocol
- 순도&문서
- References
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Help & FAQs
Biological Activity
제품 설명
IC50 & Target
[1]|
αvβ6 8 (pIC50) |
αvβ6 9.96 (pKi) |
In Vitro
GSK3335103 (43d) potently inhibits αvβ6 integrin (pIC50 = 8.0), exhibits only weak activity against other αv integrins, and shows low inhibitory effect on hERG channels[1].
The artificial membrane permeability of GSK3335103 is 146 nm/s[2].
GSK3335103 has a low intrinsic clearance, which is 20-35 mL/min/kg in rat hepatocytes and less than 21 mL/min/kg in human hepatocytes[2].
After incubation with GSK3335103 (3 μM; 60 min) at 37°C, its permeability in MDCK cells (AP/BL + efflux inhibitor) reaches 87 nm/s[2].
The kinetic solubility of GSK3335103 is ≥238 μg/mL[2].
GSK3335103 (6 h) binds with high affinity to αvβ6 integrin from recombinant human, mouse, and idiopathic pulmonary fibrosis (IPF) lung tissues[3].
GSK3335103 (2-48 h) potently inhibits αvβ6-mediated TGFβ signaling pathway by reducing pSmad2 levels[3].
GSK3335103 (0.1-16 nM) induces rapid, concentration-dependent endocytosis of αvβ6 in NHBE cells, and αvβ6 rapidly recycles back to the cell surface after drug washout; prolonged exposure, however, leads to lysosome-dependent degradation of αvβ6[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
| Species | Dose | Route | CLblood | CLunbound | T1/2 | Vss | Bioavailability | MRT | Cmax | AUC |
|---|---|---|---|---|---|---|---|---|---|---|
| Rat[1] | 1 mg/kg | i.v. | 20 mL/min/kg | 54 mL/min/kg | 4.3 h | 3.6 L/kg | / | / | / | / |
| Rat[1] | 2 mg/kg | p.o. | / | / | / | / | 93 % | / | / | / |
| Dog[1] | 1 mg/kg | i.v. | 3.7 mL/min/kg | 12 mL/min/kg | 4.8 h | 1.4 L/kg | / | / | / | / |
| Dog[1] | 1 mg/kg | p.o. | / | / | / | / | 104 % | / | / | / |
| Pig[1] | 1 mg/kg | i.v. | 5.6 mL/min/kg | 21 mL/min/kg | 2.7 h | 0.9 L/kg | / | / | / | / |
| Pig[1] | 1 mg/kg | p.o. | / | / | / | / | 84 % | / | / | / |
| Rat[2] | 1 mg/kg | i.v. | 20 mL/min/kg | 54 mL/min/kg | / | 3.6 L/kg | / | 3.0 h | / | / |
| Rat[2] | 1 mg/kg | p.o. | / | / | / | / | 93 % | / | 530 ng/mL | 776 ng·h/mL |
In Vivo
GSK3335103 (0.08-2 mg/kg; p.o.; single administration) inhibits the binding of αvβ6-specific ligands, and suppresses the TGFβ-mediated pSmad2 signaling pathway in lung tissues and bronchoalveolar lavage (BAL) cells of bleomycin-induced fibrotic mice[3].
GSK3335103 (15 mg/kg; p.o.; twice daily; for 7 consecutive days) reduces Bleomycin-induced TGFβ signaling and collagen deposition levels in the lungs of fibrotic mice to levels comparable to those in healthy control mice[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Mice[1]
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Dosage:2 mg/kg; 10 mg/kg; 15 mg/kg
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Administration:p.o.
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Result:Demonstrated sustained inhibition of pharmacodynamic and fibrotic end points across the tested dose range, with a clear link between effect and unbound plasma concentration.
Achieved >90% αvβ6 target engagement at trough concentrations, which equates to a human equivalent dose range of 10-75 mg b.i.d.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:2 mg/kg
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Administration:p.o.; single dose; 2 or 8 h prior to imaging
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Result:Reduced 111In-DTPA-A20FMDV2 binding to αvβ6 in the lungs to 78% of vehicle control at 2 h post-dosing.
Reduced 111In-DTPA-A20FMDV2 binding to αvβ6 in the lungs to 76% of vehicle control at 8 h post-dosing.
Showed no significant difference in binding reduction between the 2 h and 8 h groups.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:0.08 mg/kg; 0.15 mg/kg; 0.3 mg/kg; 0.4 mg/kg; 2 mg/kg
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Administration:p.o.; single dose; 4 h prior to collection (0.08, 0.15, 0.3, 0.4 mg/kg); p.o.; single dose; 2 h, 4 h, 8 h, 16 h, or 24 h prior to collection (2 mg/kg)
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Result:Reduced lung pSmad2/tSmad2 ratio by 45% at 2 h, 6% at 4 h, and increased the ratio by 8% at 8 h post-dosing with 2 mg/kg dose, with no significant inhibition at 16 h or 24 h.
Reduced BAL cell pSmad2/tSmad2 ratio by 76% at 2 h, 61% at 4 h, and 59% at 8 h post-dosing with 2 mg/kg dose.
Determined an in vivo IC50 of 3.5 ng/mL (pIC50 8.22) for inhibition of lung pSmad2 relative to unbound blood concentrations.
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Animal Model:C57BL/6 (male, 6-12 weeks old, 17-29 g, bleomycin-induced pulmonary fibrosis)[3]
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Dosage:15 mg/kg
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Administration:p.o.; twice daily; 7 days (starting day 14 post-bleomycin)
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Result:Significantly reduced pSmad2/tSmad2 ratios in BAL cells compared to vehicle-treated bleomycin-challenged mice.
Significantly reduced total lung collagen (measured as hydroxyproline) compared to vehicle-treated bleomycin-challenged mice.
Resulted in lung collagen levels not significantly different from those in saline-treated control mice.
Chemical Information
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CAS No. 1893340-21-0
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분자량 485.59
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화학식 C27H36FN3O4
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SMILES
O=C(O)C[C@@H](C1=CC=CC(OCCOC)=C1)CN2C[C@@](CCC3=NC4=C(CCCN4)C=C3)(F)CC2
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선적
Room temperature in continental US; may vary elsewhere.
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보관
Please store the product under the recommended conditions in the Certificate of Analysis.
순도&문서
References
[1]. Procopiou PA, et al. Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αβ Integrin Inhibitors. Journal of medicinal chemistry. 2024 Oct 10;67(19):17497-17519. [Content Brief]
[2]. Hryczanek HF, et al. Core Modifications of GSK3335103 toward Orally Bioavailable αβ Inhibitors with Improved Synthetic Tractability. Journal of medicinal chemistry. 2024 Nov 14;67(21):19689-19715. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
GSK3335103 Related Classifications
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