763113-22-0 Usage
Uses
Used in Oncology:
Olaparib is used as an anticancer agent for the treatment of germline BRCA-mediated advanced ovarian cancer. It functions as a poly ADP ribose polymerase inhibitor, blocking base excision repair (BER) and increasing cancer cell death, particularly in patients who have received three or more treatments of chemotherapy.
Used in Combination Therapy:
Olaparib is used in combination therapy with alkylating agents to enhance the effectiveness of cancer treatment. It acts as a potent inhibitor of PARP1 and PARP2, blocking BER and leading to increased cancer cell death.
Used in Radiotherapy:
Recent studies show that Olaparib increases the radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy to improve treatment outcomes for lung cancer patients.
Used in Investigational Treatments:
Olaparib is currently in various phases of investigation for the treatment of breast, gastric, prostate, pancreatic, and non-small cell lung cancer, expanding its potential applications in oncology.
Therapeutic agent of ovarian cancer
Breast and ovarian cancer is a serious public health problem which is imposing severe threat on female. In recent years, the increasing rate of breast cancer incidence of China was even 1-2% higher than that of high-incidence countries. On the other hand, ovarian cancer still remains the most serious challenge for gynecologic oncologist because no mature approach for early stage diagnosis is available now. Upon diagnosis, about 70% cases are in advanced stage. Even subjecting to effective treatment and achieving complete alleviation, there are still 70% of patients who will get recurrence issue with 5-year survival rate hovering around 30-40%. Therefore, people are attempts to establish the three-level prevention and control measures of ovarian cancer like other chronic diseases.
There is urgent need of a new medication for ovarian cancer treatment because platinum-based chemotherapy has limited drug duration before the occurrence of intolerable side effects. Olaparib, together with other PARP inhibitors under development are all oral preparations which can be better tolerated and can have more long-term applications compared with those drugs used in conventional chemotherapy. Olaparib can prevent an enzyme which participate in cellular repair, and is suitable for patients with certain genetic mutations. The drug also has good prospects in the treatment of other cancers, opening up considerable market opportunities for olaparib.
In December 19, 2014, the FDA approved novel anti-cancer drug olaparib (Lynparza) for monotherapy to the patients of advanced ovarian cancer who has undergone at least 3 rounds of chemotherapy or patients of suspected BRCA mutations. At the same time, FDA approved the quantitation and classification of diagnostic kits for the detection of mutations in BRCA1 and BRCA2, BRACAnalysis CDx. Olaparib (Lynparza) is the first PARP inhibitor drugs which has been approved by FDA.
In February 2, 2015, the European Union Food and Drug Administration (EMA) also approved olaparib to enter into market in the 28 countries of European Union including Iceland, Liechtenstein and Norway. But the indications of EMA and FDA approved are slightly different; the former is for the BRCA gene mutation cases, and also for the maintenance therapy for patients of advanced epithelial ovarian cancer who has previously received platinum-containing chemotherapy drugs and exhibit response and subject to recurrence.
Figure 1 olaparib capsule of the anticancer drug “Lynparza” developed by the AstraZeneca Company of US.
Pharmacological effects
Olaparib is a kind of novel poly ADP-ribose polymerase (PARP) inhibitors, including PARP1, PARP2, and PARP3. PARP mediates a DNA-repair mechanism which plays a important role in DNA damage repair and apoptosis, so olaparib specifically targets on the DNA repair mechanism of the targeting cell DNA repair and take effects by attacking the critical vulnerabilities of cancer cells carrying mutations in BRCA1 and BRCA2. Owing to this mechanism, it can be used for the maintenance therapy of patients of severe recurrent ovarian cancer who has breast cancer susceptibility gene (BRCA) mutation as well as being sensitive to platinum drug.
Scientists from Harvard Medical School Dana-Farber Cancer Institute have found that the target site of olaparib is the polymerase Q (POLQ, also known POLθ). Those scientists found that a large number of patients of ovarian cancer has the genetic deficiency in the homologous recombination (homologous recombination, HR) repair pathway and dramatic up-regulated expression of POLQ greatly. Since HR is an important repair pathway for repairing broken DNA, they speculated that the major function of POLQ is to compensate for the lack of HR and participate in DNA repair.
The experiment has demonstrated that, in normal HR cells, knockout of POLQ would make HR activity increase significantly; while in HR deficient cells, the knockout of POLQ leads to cell death. POLQ contains RAD51 binding domain which can block the process of RAD51-mediated DNA repair. Related research has been published in the February 12, 2015 《Nature》journal with Raphael Ceccaldi being the first author of this research.
Studies have revealed that about 10% of ovarian cancer patients and 5% of breast cancer patients contain BRCA1 or BRCA2 mutations. Both BRCA1 and BRCA2 belong to tumor suppressor genes as the major components of HR repair pathway. Their mutation suggests the loss of function for the HR repair pathway. In the cancer model of BRCA1 or BRCA2 mutations, blocking the important component for repairing single-strand DNA breaks--PARP can kill the mutated cancer cells. Put the BRCA-deficient mice with POLQ deficient mice for hybridization will cause the death of mouse embryos shortly after birth, which means that the coexistence of two repair pathway deficiency will cause embryonic lethality.
These above findings suggest that olaparib, a kind of novel oral PARP inhibitor which is able to kill BRCA deficient cells, may be the effective drug for treating cancer patients who carry such mutations. Previously, researcher’s knowledge of the BRCA mutation hasn’t influenced patients’ choice of treatment on either ovarian cancer or breast cancer. However, after the study, which means that olaparib can be used for the targeted therapy of cancer patients who carries BRCA1 or BRCA2 gene mutations with the therapeutic target site being the genetic deficiency of cancer cell genetic defect rather than a target organ.
In ovarian and breast cancer cells, BRCA mutations are the first heavy blow to the survivability of cell because it increases their susceptibility to DNA damage. Through targeting the PARP-controlled adjuvant repair pathways, olaparib and its similar drugs achieve the second heavy blow to the survivability of cell. With the disorders of both of the two repairmen signaling pathways, the accumulation of DNA damage exert the third heavy blow to the cells.
Pharmacokinetics
Absorption
After the oral administration of olaparib through its capsule preparation, it is quickly absorbed with the plasma concentration typically reaching peak at 1-3 hour period after the administration. Multiple rounds of administration cause no significant savings (savings ratio 1.4-1.5 with 2 times per day) with achieving steady-state exposure within 3 to 4 days.
Limited information suggest that, in dose across the range of 100 to 400 mg, the increase of whole body exposure (AUC) olaparib is less than direct proportion but the PK data across the test is variable.
The co-administration of a high-fat meal causes a lower absorption rate (Tmax is delayed by 2 hours), but doesn’t significantly alter the extent of absorption of olaparib (mean AUC increased by about 20%).
Distribution
After the administration of a single dose of 400 mg olaparib, the steady-state olaparib has a mean (±SD) apparent volume of distribution of 167 ± 196 L. After the achievement of the plasma concentrations at the dose of 400mg twice daily, the in vitro protein binding rate of olaparib is approximately 82%.
Metabolism
In vitro, CYP3A4 has been shown to be primary enzymes responsible for metabolism of olaparib.
After oral administration of 14C-olaparib to female patients, unchanged olaparib accounts for the majority (70%) of the circulating radioactivity in the plasma.
It is extensively metabolized in the urine and feces with the radioactivity of drug remained unchanged accounting for 15% and 6%, respectively. The biggest part of metabolism attributes to the oxidation and the derived components which subsequently bind with glucuronide or sulfate.
Excretion
After the administration of a single dose of 400 mg olaparib, it was observed of a mean (± standard deviation) terminal plasma half-life being 11.9 ± 4.8 in hours and the apparent plasma clearance being 8.6 ± 7.1L/h.
After a single dose of 14C-olaparib, during the seven days of collection, 86% of the administered radioactivity was recovered with 44% going through urine and 42% going through feces. Most of the material is excreted as metabolites.
According to the preliminary data of special efforts from renal impairment test, when olaparib is administrated by patients of mild renal impairment (CLcr = 50-80 mL/min; N = 14) and compared to patients with normal renal function (CLcr> 80 mL/min; N = 8), the mean AUC and Cmax of olaparib were increased by 1.5 and 1.2 times, respectively. There are no data available for the patients with CLcr <50 mL/min or patients subjecting to dialysis.
Drug Interactions
In vitro, olaparib is a inhibitor of the CYP3S4 but the inducing agent of CYP2B6 upon the higher concentration achieved clinically. Olaparib has small or no inhibitory effects on other CYP isozymes. In vitro studies have ever shown that olaparib is the substrate of CYP3A4.
According from a set of Drug-interaction test data (N = 57), when olaparib is administrated with itraconazole, a potent CYP3A inhibitor, in combination, the AUC and Cmax of olaparib were increased by 2.7-and 1.4-fold, respectively. The stimulation based on the physiologically pharmacokinetic (PBPK) model suggests a moderate inhibitor of CYP3A (fluconazole) can increase the AUC and Cmax of olaparib, respectively, by 2-and 1.1-fold.
According a set of Drug-interaction test data (N = 22), when olaparib is administrated with rifampicin, a potent CYP3A inducer, in combination, the AUC and Cmax of olaparib were reduced by 87% and 71 %, respectively. Stimulation based on PBPK model suggests one kind of moderate CYP3A inducers (efavirenz) may reduce the AUC and Cmax of olaparib by 50-60% and 20-30%, respectively.
In vitro studies have ever shown that olaparib is the substrate of P-gp and the inhibitors of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. It is still not clear about the clinical relevance of these findings.
The above information is edited by the lookchem of Dai Xiongfeng.
Side effects
1. The most common adverse reaction in clinical trials≥20%) include anemia, nausea, fatigue (including lack in strength), vomiting, diarrhea, taste disturbance, indigestion, headache, loss of appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort.
2. The most common laboratory abnormalities (≥25%) is increased creatinine, increased red blood cell mean volume, reduced hemoglobin, reduced lymphocytes, reduced absolute neutrophil count, and thrombocytopenia.
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
Synthesis
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.
Drug interactions
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.
Metabolism
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.
References
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
Check Digit Verification of cas no
The CAS Registry Mumber 763113-22-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 7,6,3,1,1 and 3 respectively; the second part has 2 digits, 2 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 763113-22:
(8*7)+(7*6)+(6*3)+(5*1)+(4*1)+(3*3)+(2*2)+(1*2)=140
140 % 10 = 0
So 763113-22-0 is a valid CAS Registry Number.
InChI:InChI=1/C24H23FN4O3/c25-20-8-5-15(14-21-17-3-1-2-4-18(17)22(30)27-26-21)13-19(20)24(32)29-11-9-28(10-12-29)23(31)16-6-7-16/h1-5,8,13,16H,6-7,9-12,14H2,(H,27,30)
763113-22-0Relevant articles and documents
Novel preparation method of olaparib
-
, (2021/08/11)
The invention relates to a novel preparation method of olaparib. The novel preparation method comprises the following preparation steps: 1, reacting 4-methylphthalazin-1(2H)-one with NBS and AIBN in a reaction solvent; 2, carrying out a coupling reaction on 4-(bromomethyl)phthalazin-1(2H)-one and (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid in a reaction solvent under the action of a catalyst and an alkali; 3, hydrolyzing methyl 2-fluoro-5-((4-oxo-3, 4-phthalazin-1-yl)methyl)benzoate in a reaction solvent under the action of alkali; and 4, reacting the 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazin-1-yl)methyl)benzoic acid with cyclopropyl (piperazine-1-yl)methyl ketone hydrochloride in a reaction solvent under the action of a condensing agent and alkali to obtain a crude olaparib product, and recrystallizing to obtain the high-purity olaparib. According to the process of the novel preparation method, the total yield can be effectively improved, impurities caused by cyano hydrolysis can be obviously reduced, and the purity and quality of the prepared olaparib are improved.
Novel synthesis method of olaparib bulk drug
-
, (2021/06/22)
The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.
A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides
Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels
, p. 7114 - 7123 (2021/03/03)
A series of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the success of this novel carbon isotope labeling technique is the observation that 13C-labeled NiII-acyl complexes, formed from a 13CO insertion step with NiII-alkyl intermediates, rapidly react in less than one minute with 2,2’-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters. Either the use of 13C-SilaCOgen or 13C-COgen allows for the stoichiometric addition of isotopically labeled carbon monoxide. Subsequent one-pot acylation of a series of structurally diverse amines provides the desired 13C-labeled carboxamides in good yields. A single electron transfer pathway is proposed between the NiII-acyl complexes and the disulfide providing a reactive NiIII-acyl sulfide intermediate, which rapidly undergoes reductive elimination to the desired thioester. By further optimization of the reaction parameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11 isotope labeling. Finally, this isotope labeling strategy could be adapted to the synthesis of 13C-labeled liraglutide and insulin degludec, representing two antidiabetic drugs.
Preparation method of olaparib
-
, (2019/09/17)
The invention relates to a preparation method of olaparib. 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate and a hydrazine reagent are subjected to a chemical reaction to obtain a 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid compound, then, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid and 1-cyclopropyl formylpiperazine are subjected to a condensation reaction, and olaparib is prepared. Besides, 2-(2-(4-fluoro-3-carboxylphenyl)acetyl)benzoate is firstly subjected to the condensation reaction with 1-cyclopropyl formylpiperazine and then subjected to the chemical reaction with the hydrazine reagent, and olaparib is prepared.
Preparation method of Olaparib
-
, (2018/07/30)
The invention discloses a preparation method of Olaparib. The preparation method comprises the following steps: carrying out a reaction between phthalide (II) and 3-bromo-4-fluorobenzaldehyde (III) toobtain a compound IV, carrying out a reaction between the compound IV and hydrazine monohydrate to obtain a compound V, and carrying out a reaction between the compound V and 1-cyclopropylcarbonylpiperazine to obtain the final product of Olaparib (I). The raw materials used in the reaction are cheap and easy to obtain, and the preparation method is simple in process route, high in total yield andfew in byproducts and is applicable to industrial production.
Olaparib refining method
-
, (2018/10/11)
The invention discloses an olaparib refining method, which comprises: (1) dissolving an olaparib crude product in a mixed solvent of ethyl acetate and acetone, and controlling the temperature at 45-50DEG C until olaparib is completely dissolved; (2) adding active carbon, decolorizing, filtering, cooling the filtrate to a temperature of -10-0 DEG C, crystallizing, and growing the crystal; and (3)filtering, washing the filtered solid by using acetone, and carrying out vacuum drying to obtain the refined olaparib. With the refining method of the present invention, the purity of the obtained olaparib can reach more than 99.9%, the total impurity and the single impurity are respectively controlled within 0.1% and 0.05%, the quality of the product is remarkably improved, the refining process is easy to operate, and the refining method is suitable for industrial production.
Synthetic method of olaparib
-
, (2018/07/06)
The invention discloses a synthetic method of olaparib. The synthetic method comprises the following steps: with phthalhydrazide as a starting material, reacting with phosphorus oxychloride to generate 1-chloro-4-carbonylpyridazine, and further reacting with ethyl 2-fluoro-5-bromomethylbenzoate, so as to generate ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate; and carryingout hydrolysis and acylation, and carrying out condensation reaction by virtue of ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate and 1-(cyclopropylcarbonyl)-piperazine, so asto generate olaparib. The synthetic method has the beneficial effects that phthalhydrazide is taken as the starting material for the first time, is easily available and is environmentally friendly; by utilizing Neigishi coupling, organic metal is utilized for reaction, catecholborane with a relatively high cost is not used, and zinc powder is used, so that the production cost is lowered, and thetotal yield of the route reaches 70.2%; and the reaction route is relatively short, reaction conditions are mild, and the synthetic method is suitable for industrial production.
PROCESSES FOR PREPARING OLAPARIB
-
, (2018/03/25)
Provided herein are novel processes and methods for making 4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4-fluorophenyl]methyl(2H)phthalazin-1-one (Olaparib) and intermediates thereof. Olaparib is a poly ADP ribose polymerase (PARP) inhibitor useful in the treatment of cancers. Benefits of the present disclosure include the use of less toxic compounds and improved yields.
PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
-
, (2017/12/14)
The present invention is directed to process for preparation of Olaparib of formula (I). The present invention further relates to novel polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
Olaparib compound refining method
-
, (2017/11/08)
The invention relates to an olaparib compound refining method. The method includes synthesis of a crude olaparib product and refining of olaparib. Refining includes steps: 1) adding ethyl acetate petroleum ether mixed liquid and the crude olaparib product into a reaction bottle, slowly heating to 50-55 DEG C, performing heat-preservation stirring for 20min, heating to 70-75 DEG C, stirring, and dissolving the crude product to obtain crude product solution; adding activated carbon into the crude product solution, decolorizing, filtering and collecting filtrate; 2) slowly cooling the filtrate to 20-25 DEG C, keeping the temperature and stirring; 3) cooling the filtrate to 0 DEG C or below, controlling a stirring speed at 15r/min, adding seed crystal, controlling the temperature and the stirring speed to grow the crystal for 1.5h, filtering, flushing a filter cake with a small quantity of ethyl acetate petroleum ether mixed liquid, and drying to obtain a refined olaparib product. The refining method has advantages of simple conditions, reduction of olaparib disubstituted substances, high product purity and the like.
