| Identification | Back Directory | [Name]
NVP-CLR457 | [CAS]
1453082-52-4 | [Synonyms]
NVP-CLR457
2-Oxazolidinone, 3-[2'-amino-2-(4-morpholinyl)-4'-(trifluoromethyl)[4,5'-bipyrimidin]-6-yl]-4-(hydroxymethyl)-5-methyl-, (4S,5R)-
(4S,5R)-3-[6-[2-amino-4-(trifluoromethyl)-5-pyrimidinyl]-2-(4-morpholinyl)-4-pyrimidinyl]-4-(hydroxymethyl)-5-methyl-2-oxazolidinone | [Molecular Formula]
C18H20F3N7O4 | [MOL File]
1453082-52-4.mol | [Molecular Weight]
455.39 |
| Hazard Information | Back Directory | [Uses]
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[1]. | [in vivo]
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[1].
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[1].
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[1].
Pharmacokinetic Parameters of NVP-CLR457 in male Sprague-Dawley rats[1].
| compound | 40 | | 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 [1]. Pharmacokinetic Parameters of NVP-CLR457 in female OF1 mice and male beagle dogs[1]. | species | mouse | dog | | PPB (%) | 76 | 71 | | CL (mL/min/kg) | 10 | 3 ± 0 | | Vss (L/kg) | 2 | 1.5 ± 0.2 | | t1/2 (h) | 2 | 11 ± 3 | | AUC iv (nM*h) | 3580 | 11213 ± 1169 | | AUC po (nM*h) | 1738 | 11034 ± 1531 | | oral F (%) | 49 | 98 ± 14 | | Cmax (nM) | 422 | 1121 ± 128 | | Tmax (h) | 0.5 | 1.3 ± 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 [1]. Pharmacokinetic Parameters of NVP-CLR457 in male Sprague Dawley rats, male beagle dogs[1]. | species | rat | | | dog | | | dose (mg/kg) | 3 | 30 | 100 | 0.3 | 3 | | AUC (nM*h) | 1709 ± 362 | 913 ± 251 | 784 ± 342 | 12,970 ± 1828 | 11,213 ± 1169 | | Cmax (nM) | 213 ± 61 | 41 ± 6 | 22 ± 4 | 1121 ± 128 | 309 ± 40 | | Tmax (h) | 0.5-2 | 4–24 | 24 | 1-2 | 2-24 |
| Animal Model: | Sprague Dawley rats (male)[1] | | 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[1] | | 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[1] | | 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)[1] | | 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 tumor[1]
Dosage: 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. |
| [IC 50]
PI3Kα: 12 ± 1.5 nM (IC50); PI3Kβ: 8.3 ± 1.0 nM (IC50); PI3Kδ: 8.3 ± 2.0 nM (IC50); PI3Kγ: 230 ± 31 nM (IC50) | [References]
[1] Fairhurst RA, et al. Identification of NVP-CLR457 as an Orally Bioavailable Non-CNS-Penetrant pan-Class IA Phosphoinositol-3-Kinase Inhibitor. J Med Chem. 2022 May 2. DOI:10.1021/acs.jmedchem.2c00267 |
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