Olaparib

Bezeichnung:Olaparib

CAS-Nr763113-22-0

Englisch Name:Olaparib

CBNumberCB02473811

SummenformelC24H23FN4O3

Molgewicht434.46

MOL-Datei763113-22-0.mol

Olaparib physikalisch-chemischer Eigenschaften

Dichte	1.43
storage temp.	-20°C
Löslichkeit	Soluble in DMSO (up to 33 mg/ml) or in Ethanol (up to 1.7 mg/ml)
pka	12.07±0.40(Predicted)
Aggregatzustand	solid
Farbe	Off-white
Stabilität	Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.
InChIKey	FDLYAMZZIXQODN-UHFFFAOYSA-N
SMILES	C1(=O)C2=C(C=CC=C2)C(CC2=CC=C(F)C(C(N3CCN(C(C4CC4)=O)CC3)=O)=C2)=NN1
CAS Datenbank	763113-22-0

Sicherheit

R-Sätze:	22-38-37-36
S-Sätze:	24/25-37/39
HazardClass	IRRITANT
HS Code	29339900

Gefahreninformationscode (GHS)

Olaparib Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Olaparib, marketed by AstraZeneca under the brand name Lynparza , was approved in the USA in December 2014 as a targeted, single-agent therapy for the treatment of germline BRCA-mediated advanced ovarian cancer.Olaparib, originally developed by KuDOS pharmaceuticals and later by AstraZeneca, functions as a poly ADP ribose polymerase inhibitor and has been specifically approved for patients who have received three or more treatments of chemotherapy. In clinical trials, the drug prolonged progression- free survival for patients suffering from platinum-sensitive recurrent serous ovarian cancer. Olaparib is also currently in various phases of investigation for treatment of breast, gastric, prostate, pancreatic and non-small cell lung cancer.
Chemische Eigenschaften
White Solid
Verwenden
Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor. Olaparib has been shown to induce significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Recent studies show that Olaparib increases radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy.
Definition
ChEBI: Olaparib is a member of the class of N-acylpiperazines obtained by formal condensation of the carboxy group of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid with the free amino group of N-(cyclpropylcarbonyl)piperazine; used to treat advanced ovarian cancer. It has a role as an antineoplastic agent, an EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor and an apoptosis inducer. It is a N-acylpiperazine, a member of cyclopropanes, a member of monofluorobenzenes and a member of phthalazines.
Biologische Aktivität
Many of the products generated by alkylating agents on DNA can be efficiently repaired by normal base excision repair (BER). Some poly(ADP-ribose) polymerases (PARPs) assist in the repair of single-strand DNA nicks, an important step in BER. Olaparib is a potent inhibitor of PARP1 and PARP2 (IC50 = 5 and 1 nM, respectively) but is less effective against the PARP tankyrase-1 (IC50 = 1.5 μM). It can be used in cells and in animals, alone or in combination therapy with alkylating agents, to block BER and increase cancer cell death.[Cayman Chemical]
Clinical Use
Human poly (ADP-ribose) polymerase enzymes inhibitor:
Treatment of platinum-sensitive relapsed BRCAmutated high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer
Synthese
This optimized synthesis begins with reaction of commercially available dimethyl phosphite and 2-carboxybenzaldehyde (201) to generate the corresponding phosphonate ester in 95% yield and 95% purity after aqueous workup.190 Addition of aldehyde 202 to this phosphonate ester intermediate in the presence of triethylamine led to formation of olefins 203a/203b in 96% yield as a 1:1 mixture of E/Z isomers. From olefins 203a/203b, a one-pot, three-step sequence was next performed to provide access to dihydrophthalazinyl acid 204. First, lactone ring-opening and nitrile hydrolysis was facilitated by reaction with aqueous sodium hydroxide under elevated temperatures, allowing for subsequent in situ formation of the corresponding dihydrophthalazine intermediate after addition of hydrazine hydrate. Acidification and precipitation of product with 2 N HCl led to isolation of the desired material in 77% yield and 96% purity after filtration. Further coupling of carboxylic acid 204 with Bocpiperazine (205) (HBTU, DIPEA, DMA) and subsequent removal of the carbamate with HCl/EtOH provided intermediate 206 in 46% yield from 204, relying on a pH-controlled workup procedure to enable isolation of material in high purity (94%) without requiring chromatography. The final step of the olaparib synthesis was completed via treatment of piperazine 206 with cyclopropane carbonyl chloride (207) and triethylamine, leading to isolation of olaparib in 90% yield and 99.3% purity after distillation.
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - avoid or reduce olaparib dose to 150 mg twice daily; avoid with rifabutin and rifampicin.
Antidepressants: avoid with St John’s wort.
Antiepileptics: avoid with carbamazepine, phenobarbital and phenytoin.
Antifungals: concentration increased by itraconazole and possibly fluconazole - avoid or reduce olaparib dose to 150 mg twice daily.
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.
Antivirals: concentration possibly increased by boceprevir, ritonavir and telaprevir - avoid or reduce olaparib dose to 150 mg twice daily; avoid with nevirapine.
Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - avoid or reduce olaparib dose to 150 mg twice daily.
Cobicistat: concentration possibly increased - avoid or reduce olaparib dose to 150 mg twice daily.
Grapefruit juice: avoid concomitant use.
Oestrogens and progestogens: possibly reduced contraceptive effect.
Stoffwechsel
In vitro, CYP3A4 was shown to be the main enzyme responsible for the metabolism of olaparib. The majority of the metabolism was due to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
Following a single dose of [14C]-olaparib, approximately 86% of the dose was recovered within a 7-day collection period, approximately 44% via the urine and 42% via the faeces. The majority of olaparib was excreted as metabolites.
Lager
Store at -20°C
Mode of action
Olaparib is a small molecule inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential chemosensitizing, radiosensitizing, and antineoplastic activities. Olaparib selectively binds to and inhibits PARP, inhibiting PARP-mediated repair of single strand DNA breaks; PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins and can be activated by single-stranded DNA breaks.
Einzelnachweise
1) Menear?et al. (2008),?4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose)polymerase-1;? J. Med. Chem.,?51?6581
2) Rottenberg?et al. (2008),?High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs; Proc. Natl. Acad. Sci. USA,?105?17079
3) Avila-Arroyo?et al. (2015),?Synergistic effect of Trabectedin and Olaparib combination regimen in breast cancer cell lines; J. Breast Cancer,?18?329
4) Xu?et al. (2015),?Combined olaparib and oxaliplatin inhibits tumor proliferation and induces G2/M arrest and γ-H2AX foci formation in colorectal cancer; Onco. Targets Ther.,?8?3047
5) Ghonim?et al. (2015),?PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice; Clin. Sci.(Lond),?129?951

Olaparib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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