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编 号：F745354
分子式：C18H20F3N7O4
分子量：455.39
分子式：C18H20F3N7O4
分子量：455.39
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CAS No: 1453082-52-4
产品详情
生物活性：
NVP-CLR457 (compound 40) is an orally active, potent and balanced pan-class I PI3K inhibitor. NVP-CLR457 shows a clear dose-dependent PK/PD/efficacy relationship. NVP-CLR457 has antitumor activity.
体内研究：
NVP-CLR457 (compound 40) (athymic nude mice bearing xenotransplanted Rat1-myr-p110α tumors, 3-20 mg/kg, PO, daily for 8 days) shows a dose-dependent inhibition of tumor growth.NVP-CLR457 (Mice bearing xenograft HBRX2524 human primary breast tumor, 40 mg/kg, PO, daily for 15 days) inhibits the tumor growth throughout the study.NVP-CLR457 (male Sprague-Dawley rats, 1.0 mg/kg, IV; 3.0 mg/kg, PO; once) shows high level of oral exposure and bioavailability.Pharmacokinetic Parameters of NVP-CLR457 in male Sprague-Dawley rats.compound40
CL (mL/min/kg)22 ± 6
Vss (L/kg)4.4 ± 0.2
t1/2 (h)3.3 ± 0.2
AUC iv (nM*h)1770 ± 443
oral F (%)97 ± 20
HDM FA (%)37
NVP-CLR457 (3 mg/kg (IV) and 10 mg/kg (PO) for female OF1 mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for male beagle dogs, once) shows low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability.Pharmacokinetic Parameters of NVP-CLR457 in female OF1 mice and male beagle dogs.speciesmousedog
PPB (%)7671
CL (mL/min/kg)103 ± 0
Vss (L/kg)21.5 ± 0.2
t1/2 (h)211 ± 3
AUC iv (nM*h)358011213 ± 1169
AUC po (nM*h)173811034 ± 1531
oral F (%)4998 ± 14
Cmax (nM)4221121 ± 128
Tmax (h)0.51.3 ± 0.6
NVP-CLR457 (0.3-100 mg/kg, PO, once) leads to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values.Pharmacokinetic Parameters of NVP-CLR457 in male Sprague Dawley rats, male beagle dogs.speciesratdog
dose (mg/kg)3301000.33
AUC (nM*h)1709 ± 362913 ± 251784 ± 34212,970 ± 182811,213 ± 1169
Cmax (nM)213 ± 6141 ± 622 ± 41121 ± 128309 ± 40
Tmax (h)0.5-24–24241-22-24
Animal Model:Sprague Dawley rats (male)
Dosage:1 mg/kg (IV), 3 mg/kg (PO)
Administration:IV or PO, once (Pharmacokinetic Analysis)
Result:Showed high level of oral exposure and bioavailability.
Animal Model:Female OF1 mice, male beagle dogs
Dosage:3 mg/kg (IV) and 10 mg/kg (PO) for mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for dogs
Administration:IV or PO, once (Pharmacokinetic Analysis)
Result:Showed low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability.
Animal Model:Male Sprague Dawley rats, male beagle dogs
Dosage:0.3, 3, 30, 100 mg/kg
Administration:PO, once (Pharmacokinetic Analysis)
Result:Led to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values when it formulated as a suspension of the crystalline material.
Animal Model:Female athymic nude mice (bearing xenotransplanted Rat1-myr-p110α tumors)
Dosage:3, 10, and 20 mg/kg
Administration:PO, daily for 8 days
Result:Observed dose-dependent exposure and PD responses, and showed a dose-dependent inhibition of tumor growth. The 3 mg/kg dose achieved 80% S473P-Akt inhibition only at the 1 h time point; the 10 mg/kg dose at the 1 and 4 h time points; and the 20 mg/kg at the 1, 4, and 10 h time points, with a high level of inhibition remaining at the 14 h time point (76%).
Animal Model:Mice bearing xenograft HBRX2524 human primary breast tumorDosage: 40 mg/kg
Dosage:40 mg/kg
Administration:PO, daily for 15 days
Result:Inhibited the tumor growth throughout the study, and showed a significant level of regression the end of the 15 day treatment period.
体外研究：
NVP-CLR457 (compound 40) shows the mTOR activity, with an IC50 of 2474 ± 722 nM, and inhibits RPS6 phosphorylation with an IC50 of 1633 ± 54 nM.NVP-CLR457 has no impact on the DDR response at concentrations of 1 and 5 μM.NVP-CLR457 has no effect on the rate of microtubule polymerization.
NVP-CLR457 (compound 40) is an orally active, potent and balanced pan-class I PI3K inhibitor. NVP-CLR457 shows a clear dose-dependent PK/PD/efficacy relationship. NVP-CLR457 has antitumor activity.
体内研究：
NVP-CLR457 (compound 40) (athymic nude mice bearing xenotransplanted Rat1-myr-p110α tumors, 3-20 mg/kg, PO, daily for 8 days) shows a dose-dependent inhibition of tumor growth.NVP-CLR457 (Mice bearing xenograft HBRX2524 human primary breast tumor, 40 mg/kg, PO, daily for 15 days) inhibits the tumor growth throughout the study.NVP-CLR457 (male Sprague-Dawley rats, 1.0 mg/kg, IV; 3.0 mg/kg, PO; once) shows high level of oral exposure and bioavailability.Pharmacokinetic Parameters of NVP-CLR457 in male Sprague-Dawley rats.compound40
CL (mL/min/kg)22 ± 6
Vss (L/kg)4.4 ± 0.2
t1/2 (h)3.3 ± 0.2
AUC iv (nM*h)1770 ± 443
oral F (%)97 ± 20
HDM FA (%)37
NVP-CLR457 (3 mg/kg (IV) and 10 mg/kg (PO) for female OF1 mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for male beagle dogs, once) shows low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability.Pharmacokinetic Parameters of NVP-CLR457 in female OF1 mice and male beagle dogs.speciesmousedog
PPB (%)7671
CL (mL/min/kg)103 ± 0
Vss (L/kg)21.5 ± 0.2
t1/2 (h)211 ± 3
AUC iv (nM*h)358011213 ± 1169
AUC po (nM*h)173811034 ± 1531
oral F (%)4998 ± 14
Cmax (nM)4221121 ± 128
Tmax (h)0.51.3 ± 0.6
NVP-CLR457 (0.3-100 mg/kg, PO, once) leads to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values.Pharmacokinetic Parameters of NVP-CLR457 in male Sprague Dawley rats, male beagle dogs.speciesratdog
dose (mg/kg)3301000.33
AUC (nM*h)1709 ± 362913 ± 251784 ± 34212,970 ± 182811,213 ± 1169
Cmax (nM)213 ± 6141 ± 622 ± 41121 ± 128309 ± 40
Tmax (h)0.5-24–24241-22-24
Animal Model:Sprague Dawley rats (male)
Dosage:1 mg/kg (IV), 3 mg/kg (PO)
Administration:IV or PO, once (Pharmacokinetic Analysis)
Result:Showed high level of oral exposure and bioavailability.
Animal Model:Female OF1 mice, male beagle dogs
Dosage:3 mg/kg (IV) and 10 mg/kg (PO) for mice, 0.1 mg/kg (IV), 0.3 mg/kg (PO) for dogs
Administration:IV or PO, once (Pharmacokinetic Analysis)
Result:Showed low clearance, moderate volume of distribution, and rapid absorption leading to moderate to long half-lives and high oral bioavailability.
Animal Model:Male Sprague Dawley rats, male beagle dogs
Dosage:0.3, 3, 30, 100 mg/kg
Administration:PO, once (Pharmacokinetic Analysis)
Result:Led to under-proportional increases in exposure (both AUC and Cmax) and much longer Tmax values when it formulated as a suspension of the crystalline material.
Animal Model:Female athymic nude mice (bearing xenotransplanted Rat1-myr-p110α tumors)
Dosage:3, 10, and 20 mg/kg
Administration:PO, daily for 8 days
Result:Observed dose-dependent exposure and PD responses, and showed a dose-dependent inhibition of tumor growth. The 3 mg/kg dose achieved 80% S473P-Akt inhibition only at the 1 h time point; the 10 mg/kg dose at the 1 and 4 h time points; and the 20 mg/kg at the 1, 4, and 10 h time points, with a high level of inhibition remaining at the 14 h time point (76%).
Animal Model:Mice bearing xenograft HBRX2524 human primary breast tumorDosage: 40 mg/kg
Dosage:40 mg/kg
Administration:PO, daily for 15 days
Result:Inhibited the tumor growth throughout the study, and showed a significant level of regression the end of the 15 day treatment period.
体外研究：
NVP-CLR457 (compound 40) shows the mTOR activity, with an IC50 of 2474 ± 722 nM, and inhibits RPS6 phosphorylation with an IC50 of 1633 ± 54 nM.NVP-CLR457 has no impact on the DDR response at concentrations of 1 and 5 μM.NVP-CLR457 has no effect on the rate of microtubule polymerization.
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