IPI 145
- CAS NO.:1201438-56-3
- Empirical Formula: C22H17ClN6O
- Molecular Weight: 416.86
- MDL number: MFCD15144635
- EINECS: 200-256-5
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-05-22 15:18:35
What is IPI 145?
Absorption
Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9. The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile.
Toxicity
Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy.
Description
Duvelisib (1201438-56-3) is a potent and selective (IC50’s: PI3Kα = 1602nM, PI3Kβ = 85nM, PI3Kδ= 2.5nM, PI3Kγ = 27nM) dual PI3Kδ/γ inhibitor.1 It inhibits B and T cell proliferation, blocks neutrophil migration, and inhibits basophil activation. Duvelisib antagonizes B-cell receptor cross-linking activated pro-survival signals in primary chronic lymphocytic leukemia cells.2?Duvelisib also shows preclinical/clinical activity against other hematologic malignancies such as Non-Hodgkins lymphoma, T-cell lymphoma, and others.3,4?Useful clinical agent for the treatment of various blood cancers. Low-dose treatment of T-cell-inflamed tumor models of head and neck cancers with Duvelisib enhanced responses to PD-L1 blockade via suppression of myeloid-derived suppressor cells.5?Higher doses reversed the effect due to suppression of tumor-infiltrating T lymphocytes
The Uses of IPI 145
IPI 145 is an 1,2-dihydroisoquinolin-1(2H)-one derivative and has been developed as a modulator of PI3 kinase.
Indications
Duvelisib is indicated for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have trialed at least two prior therapies.
Background
Duvelisib, also known as IPI-145 and INK-1197, is a small-molecule inhibitor of phosphoinositide-3 kinases that was designed initially to prove that simultaneous inhibition of the isoforms delta and gamma can produce a broad adaptative and innate immune cell inhibitory activity. All the work around duvelisib showed that this agent is a potent inhibitor of both forms. Duvelisib was developed by Verastem, Inc and FDA approved on September 24, 2018.
Definition
ChEBI: 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone is a member of isoquinolines.
brand name
Copiktra
General Description
Class: lipid kinase; Treatment: CLL, SLL, FL; Other name: INK1197, IPI145; Oral bioavailability = 42%; Elimination half-life = 4.7 h; Protein binding = 98%
Pharmacokinetics
Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib.
In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab.
In clinical trials of follicular lymphoma, duvelisib presented and overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months.
Pharmacokinetics
The recommended dose of duvelisib is 25 mg twice daily, much lower than that of idelalisib (150 mg, bid). Duvelisib is rapidly absorbed, with a peak concentration after 1–2 h. Following the administration of 25 mg of duvelisib, the absolute bioavailability in healthy volunteers is 42%. It is eliminated with a short half-life of 4.7 h, thus requiring twice daily administration.
Metabolism
Duvelesib is mainly metabolized by CYP3A4.
Metabolism
Duvelisib is
primarily metabolized by CYP3A4 to give a monooxidation product, IPI-656, which has no
pharmacologically relevant activity.
References
1) Winkler?et al.?(2013),?PI3K-δ and PI3K-γ Inhibition by IPI-145 Abrogates Immune Response and Suppresses Activity in Autoimmune and Inflammatory Disease Models;?Chem. Biol.?20?1309 2) Dong?et al.?(2014),?IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells;?Blood?124?3583 3) Flinn?et al.?(2018),?Duvelisib, a novel dual inhibitor of PI3K-δ/γ, is clinically active in advances hematologic malignancies;?Blood?131?877 4) Faia?et al.?(2018),?The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib, shows preclinical synergy with multiple targeted therapies in hematologic malignancies;?PLoS One?13?e0200725 5) Davis?et al.?(2017),?Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ;?Cancer Res.?77?2607
Properties of IPI 145
Melting point: | 205-206o C |
Boiling point: | 757.8±60.0 °C(Predicted) |
Density | 1.474±0.06 g/cm3(Predicted) |
storage temp. | -20°C |
solubility | Soluble in DMSO (up to at least 25 mg/ml) |
pka | 10.05±0.10(Predicted) |
form | White solid. |
color | White |
Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. |
Safety information for IPI 145
Computed Descriptors for IPI 145
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