1146702-54-6 Usage
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.
Clinical Use
Phosphatidylinositol 3-kinase p110δ (PI3Kδ) inhibitor:
Treatment of chronic lymphocytic leukaemia (CLL)
and follicular lymphoma (FL)
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.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin
- avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin and phenytoin - avoid.
Antipsychotics: avoid with clozapine, increased
risk of agranulocytosis; avoid with pimozide and
quetiapine.
Metabolism
Idelalisib is metabolised mainly via aldehyde oxidase, and
to a lesser extent via CYP3A and UGT1A4. The primary
and only circulating metabolite, GS-563117, is inactive
against PI3Kδ.
Following a single 150 mg oral dose of [14C]-labelled
idelalisib, approximately 78% and 15% was excreted
in faeces and urine, respectively. Unchanged idelalisib
accounted for 23% of total radioactivity recovered in urine
over 48 hours and 12% of total radioactivity recovered in
faeces over 144 hours.
Check Digit Verification of cas no
The CAS Registry Mumber 1146702-54-6 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,4,6,7,0 and 2 respectively; the second part has 2 digits, 5 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 1146702-54:
(9*1)+(8*1)+(7*4)+(6*6)+(5*7)+(4*0)+(3*2)+(2*5)+(1*4)=136
136 % 10 = 6
So 1146702-54-6 is a valid CAS Registry Number.
1146702-54-6Relevant articles and documents
Synthesis and biological evaluation of novel purinyl quinazolinone derivatives as PI3Kδ-specific inhibitors for the treatment of hematologic malignancies
Kim, Yeon Su,Cheon, Min Gyeong,Boggu, Pulla Reddy,Koh, Su Youn,Park, Gi Min,Kim, Gahee,Park, Seo Hyun,Park, Sung Lyea,Lee, Chi Woo,Kim, Jong Woo,Jung, Young Hoon
, (2021/08/04)
Phosphatidylinositol 3-kinases (PI3Ks) mediate intracellular signal transduction. Aberrant PI3K signaling is associated with oncogenesis and disease progression in solid tumors and hematologic malignancies. Idelalisib (1), a first-in-class PI3Kδ inhibitor for the treatment of hematologic malignancies, was developed, but its sales were limited by black box warnings due to unexpected adverse effects. Therefore, to overcome these adverse events, various quinazolinone derivatives were synthesized and evaluated in vitro based on their inhibitory activity against the PI3K enzyme and the viability of cell lines such as MOLT and SUDHL. Among them, 6f (IC50 = 0.39 nM) and 6m (IC50 = 0.09 nM) showed excellent enzyme activity, and 6m displayed an approximately four-fold higher selectivity for PI3Kγ/δ compared with Idelalisib (1). Furthermore, in vivo PK experiments with 6f and 6m revealed that 6f (AUClast = 81.04 h*ng/mL, Cmax = 18.34 ng/mL, Tmax = 0.5 h, t1/2 = 10.2 h in 1 mpk dose) had improved PK compared with 1. Finally, further experiments will be conducted with 6f selected as a candidate, and the potential for it to be developed as a treatment with good efficacy for hematologic malignancies will be determined.
