Uses
IPI 145 is an 1,2-dihydroisoquinolin-1(2H)-one derivative and has been developed as a modulator of PI3 kinase.
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
Definition
ChEBI: 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone is a member of isoquinolines.
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).
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
