Ceritinib
(Zykadia ®
)
Rearch code: LDK-378
1 General Information
● Ceritinib is a kina inhibitor, which was first approved in
2014 by US FDA.
雅思考点
● Ceritinib was discovered and marketed by Novartis. ● Ceritinib inhibited autophosphorylation of ALK, ALK-me-
diated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent
cancer cells.
● Indicated for the treatment of patients with anaplastic lym-
phoma kina (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progresd on or are intol-erant to crizotinib.
● Available as capsules with each containing 150 mg of
ceritinib and recommended do is 750 mg once daily until dia progression or unacceptable toxicity.
Key Approvals around the World *
First approval
date 04/29/2014 06/05/2015 NDA NO. 205755 EMEA/H/C/003819
Brand name Zykadia ® Zykadia ® Indication NSCLC NSCLC
Authorisation holder
Novartis
Novartis Europharm Ltd
*
Till Dec 2015, it has not been approved by PMDA (Japan) and CFDA (China).
Worldwide Sales
Active Ingredient
Molecular formula : C 28H 36N 5O 3ClS Molecular weight : 558.14 CAS No.: 1032900-25-6
Chemical name : 5-Chloro-N 4-[2-[(1methylethyl)sul-fonyl]phenyl]-N 2-[5-methyl-2-(1-methylethoxy)-4-(4-pi-peridinyl)phenyl]-2,4-pyrimidinediamine Parameters of Lipinski's “Rule of 5”
558
3
江苏陪产假8
页眉横线怎么删7
114
4.70 ± 0.95
a
Calculated by ACD/Labs software V11.02.
Drug Product *
Dosage route : Oral Strength : 150 mg Dosage form : Capsule
Inactive ingredient : Colloidal anhydrous silica, L-hydroxy-propylcellulo, magnesium stearate, microcrystalline cel-lulo, and sodium starch glycolate, gelatin, indiogotine, and titanium dioxide Recommended do :
The recommended starting do is 750 mg once daily with-out food.
Discontinue ceritinib for patients unable to tolerate 300 mg daily.
If a do of ceritinib is misd, make up that do unless the next do is due within 12 h.
*
Sourced from the FDA drug label information.
2 ▐2014 Worldwide NCEs
Key Patents
Patents Summary
•Ceritinib’s compound patent application was filed as PCT application by IRM in 2007.
•The compound patent will be expired in 2027 originally, which has been granted in Japan, Europe, the United States successively.
•Zykadia® (Ceritinib) has got five years NCE market exclusivity protection and ven years ODE after it was approved by FDA in Apr. 29, 2014 initially.
Patents List
Ceritinib ▐ 3
2 Chemistry
Route 1: Original Discovery Route
Synthetic Route: The overall synthetic route of ceritinib was enabled via a modified Buchwald-Hartwig coupling of two advanced intermediates aryl amino-piperidine 6 and arylsulfonyl chloro-pyrimidine 7. Aryl amino-piperidine 6 was synthesized in five stepsfrom 2-chloro-4-fluorotoluene 1. Nitration of 1 using KNO3/H2SO4 yielded the corresponding nitro derivative 2 in a 71% yield. Condensation of compound 2 with iso propanol in the prence of Cs2CO3 provided the 2-chloro-4-iso propoxy-5-nitrotol-uene 3 in excellent yield. Suzuki coupling of compound 3 with 4-pyridineboronic acid 4 provided compound 5 in 73% yield. Concomitant reduction of pyridine and nitro group using PtO2/H2 afforded the corresponding piperidine-aniline intermediate, which was subquently protected with Boc, generating compound 6 in 60% over two steps. Buchwald-Hartwig coupling of 6 with arylsulfonyl chloro-pyrimidine 7 provided the precursor of ceritinib. Boc deprotection with TFA, concentration, and sub-quent precipitation with 1 N HCl yielded ceritinib as the HCl salt in 35.0% yield from 6 and the overall yield of 10.3%.[1, 2] Synthesis of the required aryls
ulfonyl chloro-pyrimidine coupling precursor 7 began with 2-(isopropylsulfonyl)benzenamine 8 and 2,4,5-trichloropyrimidine 9 under basic condition (NaH, DMF, DMSO)in 60% yield.
[1] Marsilje, T. H.; Pei, W.; Chen, B., et al. J. Med. Chem.2013,56, 5675-5690.
[2] Michellys, P.-Y.; Pei, W.; Marsilje, T. H., et al. WO2008073687A2, 2008.
4 ▐2014 Worldwide NCEs
Route 2:
Synthetic Route: In this strategy, ceritinib was prepared from reduction of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine 1 under Pd/C H2 condition afforded corresponding phenylamine 2 in 92% yield. Then Sandmeyer reaction was carried out in the prence of NaNO2/CuBr/HBr/H2O to give 4-(4-bromo-5-isopropoxy-2-methylphenyl)piperidine 3 in 83% yield. Buckward-Hartwig coupling of 3 with 5-chloro-4-nitropyrimidin-2-amine 4 converted to desired compound 5 in 78% yield, which was hy-drogenated and coupled with 1-bromo-2-(isopropylsulfonyl)benzene 7 to obtain the target ceritinib in 74% yield over two steps. The overall yield was 44%.[3]
3 Pharmacology
win7怎么录屏Summary
Mechanism of Action
●Ceritinib is a kina inhibitor, which inhibited ALK, insulin-like
growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and
ROS1.
●Ceritinib was approximately 50-fold more specific for ALK
(IC50 = 0.15 nM) than InsR (IC50 = 7 nM) and IGF-1R (IC50 = 8
nM), other members of theinsulin receptor superfamily.
●Ceritinib inhibited autophosphorylation of ALK, ALK-mediated
phosphorylation of the downstream signaling protein STAT3,
and proliferation of ALK-dependent cancer cells.
●The off-target activity of ceritinib was evaluated for 42 of the
target receptors (MC4, IC50 = 0.6 nM), 84 of the broad spectrum
screen receptors (transporter monoamine, inhibition = 97%), and
10 of the GPCRs (dopamine 2 receptor, IC50 = 4000 nM).
[3] Xuenong, X. CN103992262A, 2014.
古开头的成语
Ceritinib ▐ 5 In Vitro Efficacy
●Anti-proliferative activity of ceritinib in tumor cell lines:
Cell lines expresd with ALK fusion protein: IC50 = 11-56 nM.
Cell lines expresd with EML4-ALK-mutation: IC50 = 37.6-250 nM.
Ba/F3 cells expresd with others fusion proteins: IC50 = 180-400 nM.
●Phosphorylation of ceritinib in Karpas299 cells:
ALK protein: IC50 = 46 nM.
STAT3 protein: IC50 = 150 nM.理工科
In Vivo Efficacy
●H2228 cells xenograft models:
In SCID mice: Significance at dos ≥6.25 mg/kg. Complete tumor regression with 25 mg/kg ceritinib after 14 days.
In nude rats: Significance at dos ≥10 mg/kg.
●Karpas299 cells xenograft models:
In SCID mice: Significance at dos ≥12.5 mg/kg. Complete tumor regression with 25 mg/kg ceritinib after 14 days.
In nude rats: Significance at dos ≥12.5 mg/kg. Complete tumor regression with 25 mg/kg ceritinib after 14 days.
●Crizotinib-resistant H2228 cells xenograft model carrying the ALK-mutation in SCID mice:
Non-ALK-mutation: Significant at dos ≥50 mg/kg.
I1171T ALK-mutation: Significant at dos ≥25 mg/kg.
C1156Y ALK-mutation: Significant at dos ≥50 mg/kg.
Mechanism of Action
Table 1In Vitro Effects of Ceritinib and Crizotinib on Human Protein Kinas[4]
EPK CE ALK (1066-1459) Y a0.15 3 EPK CE AXL Y 180 13
EPK CE IGF-1R (980-1369) Y 8 400 EPK CE RET (658-1072) Y 400 2200 EPK CE INSR (871-1343) Y 7 290 EPK ROCK2 S/T 450 2500
EPK AURORA_A S/T b110 600 EPK CE FGFR3
(411-K650E-806) Y 430 1700
EPK cABLT315 Y 130 6
The applicant evaluated the lectivity of ceritinib and crizotinib by testing its in vitro activity against 36 recombinant human protein kinas using the Caliper mobility shift assay, table 1 showed ceritinib most lective for ALK (IC50 <0.5 μM). a Y: Tyrosine-specific protein kinas. b S/T: Serine/Threonine-specific protein kinas.
[4]
H2 receptor 170 NA
monoamine
Rabbit 10 μM 97 331
Opk receptor 570 NA K channel[Ka] Rat 10 μM 99 682
学习对联MC3 receptor 670 NA Somatostatin sst1 Human 10 μM 88 2420
MC4 receptor 600 35% at 10 μM Somatostatin sst2 Human 10 μM 76 2250
Ad3 receptor 730 8300 Somatostatin sst3 Human 10 μM 93 5120
NK1 receptor 990 79% at 30 μM Somatostatin sst4 Human 10 μM 90 1880
D2 receptor 1200 NA 5-HT5A Human 10 μM 71 5000 The off-target activity of ceritinib was evaluated using an in vitro safety pharmacology profiling panel including 139 G protein-coupled receptors (GPCRs), ion channels, nuclear receptors, transporters, and enzymes that have been previously linked to potential side effects. At least eight concentrations of ceritinib were tested. The agonist and antagonist activities of ceritinib were evaluated for 10 GPCRs using a safety pharmacology screen. A fluorometric imaging plate reader (FLIPR) assay was conducted with a four-fold, eight-point rial dilution of ceritinib up to 10 μM to a sss agonist and antagonist activity. Ceritinib showed weak agonist activity on the dopamine D2 receptor (EC50 = 6 μM, IC50 = 4 μM), but did not exhibit significant activity against the other GPCRs tested. a Ceritinib interacted with 42 of the target receptors, table 2 showed the target receptors IC50 <1500 nM. b A safety pharmacology broad spectrum screen with 84 receptors at ceritinib was tested at 10 μM in duplicate,
table 2 showed the broad spectrum receptors inhibited >70%.
范仲淹读书[4] U.S. Food and Drug Adminstration (FDA) Datada. www.v/drugsatfda_docs/nda/2014/205755Orig1s000PharmR.pdf (accesd
Nov 2015).
