CAL-101

Description

Idelalisib is an orally available selective and potent phosphatidylinositol 3-kinase δ (PI3 Kδ) inhibitor originally developed by Calistoga Pharmaceuticals, which was acquired by Gilead in April 2014. In July 2014, the drug was approved in the USA for the treatment of relapsed chronic lymphocytic leukemia as well as several oncology orphan drug designations. Since idelalisib specifically inhibits PI3Kd, which is expressed primarily in bloodcell lineages, the therapeutic effect is localized, limiting interference with PI3K isoform signaling that is critical to normal function of healthy cells.

Indications

Among the large groups of structural diverse lipid kinase inhibitors, especially against PI3Ks, idelalisib (Zydelig(R), Gilead Sciences) is the only inhibitor approved by FDA for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab and patients with relapsed follicular B-cell non-Hodgkin lymphoma or small lymphocytic lymphoma.

brand name

Zydelig

General Description

Class: lipid kinase; Treatment: CLL, SLL, FL; Other name: CAL-101, GS-1101; Elimination half-life = 8.2 h; Protein binding > 84%

Pharmacokinetics

The recommended dose of idelalisib is 150 mg orally twice a day, consistent with its elimination halflife is 8.2 h (Table 2). It is absorbed rapidly with a t_max of 1.5 h. Idelalisib is metabolized by aldehyde oxidase and CYP3A to give a major metabolite GS- 563117 (Fig. 7), which is inactive against P110δ and other isoforms.

Synthesis

Commercial 2-fluoro-6-nitrobenzoic acid (117) was treated with oxalyl chloride in the presence of catalytic amount of N,Ndimethylformamide (DMF) in DCM to give the corresponding 2- fluoro-6-nitrobenzoyl chloride as a brown syrup, which was subsequently coupled with aniline under Schotten-Baumann conditions to yield 2-fluoro-6-nitro-N-phenylbenzamide 118 in 99% yield. Coupling of 118 with commercial N-Boc-2(S)-aminobutyric acid in the presence of Et3N in DCM generated imide 119 in 66% yield. Reductive cyclization of nitro imide 119 by means of zinc dust in acetic acid gave the cyclized quinazolinone 120 in 69% yield, which underwent immediate N-deprotection with TFA in DCM to furnish the corresponding free amine 121. Finally, a substitution reaction involving amine 121 and 6-bromopurine (122) in the presence of DIPEA in t-BuOH gave idelalisib (XV) as a solid in 50% yield.

target

PI3Kδ

IC 50