IPI 145 Chemical Properties

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)

form 

White solid.

pka

10.05±0.10(Predicted)

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.

InChI

InChI=1S/C22H17ClN6O/c1-13(28-21-19-20(25-11-24-19)26-12-27-21)17-10-14-6-5-9-16(23)18(14)22(30)29(17)15-7-3-2-4-8-15/h2-13H,1H3,(H2,24,25,26,27,28)/t13-/m0/s1

InChIKey

SJVQHLPISAIATJ-ZDUSSCGKSA-N

SMILES

C1(=O)C2=C(C=CC=C2Cl)C=C([C@@H](NC2=C3C(=NC=N2)NC=N3)C)N1C1=CC=CC=C1

IPI 145 Usage And Synthesis

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

Uses

IPI 145 is an 1,2-dihydroisoquinolin-1(2H)-one derivative and has been developed as a modulator of PI3 kinase.

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

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.

Synthesis

IPI145 Intermediate-5 (Compound 10) (200 g) was taken as raw material and suspended in a solvent mixture of ethanol (900 mL; 4.5 v/v) and water (300 mL; 1.5 v/v) at 22 °C. Subsequently, concentrated hydrochloric acid (300 mL; 1.5 v/v) was slowly added and the reaction was stirred at 25-35 °C for 1.5 h until all solids were completely dissolved to form a dark brown solution. Upon completion of the reaction, ammonium hydroxide (260 mL) was added to adjust the pH to 8-9. Next, the product seed of polycrystalline type C (0.5 g) was added (type A seed could also be used) and the reaction system was maintained for 10 min, followed by the slow addition of water (3 L; 15 v/v) over a period of 2 h to induce crystallization. The reaction mixture was continued to be stirred at 20-25 °C for 3.5 h and then filtered. The filter cake was washed sequentially with water (1 L; 5 v/v) and heptane (800 mL; 4 v/v), and finally dried under vacuum at 52 °C for 23 h. The target product (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenyl-1(2H)-isoquinolone was obtained as 155.5 g, in 93.5% yield, with a purity of 99.6% (AUC), and an p enantiomeric excess value of 93.8% (chiral HPLC).

target

PI3Kγ/δ

IC 50

Metabolism

Duvelisib is primarily metabolized by CYP3A4 to give a monooxidation product, IPI-656, which has no pharmacologically relevant activity.

References

[1] DAVID G WINKLER. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.[J]. Chemistry & biology, 2013, 20 11: 1364-1374. DOI:10.1016/j.chembiol.2013.09.017
[2] SHUAI DONG. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.[J]. Blood, 2014, 124 24: 3583-3586. DOI:10.1182/blood-2014-07-587279
[3] IAN W FLINN. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies.[J]. Blood, 2018, 131 8: 877-887. DOI:10.1182/blood-2017-05-786566
[4] KERRIE FAIA. The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies.[J]. ACS Applied Bio Materials, 2018: e0200725. DOI:10.1371/journal.pone.0200725
[5] RUTH J DAVIS. Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ.[J]. Cancer research, 2017, 77 10: 2607-2619. DOI:10.1158/0008-5472.can-16-2534

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