KU 59436
Olaparib
CAS: 763113-22-0;937799-91-0
Molecular Formula: C24H23FN4O3
KU 59436 - Names and Identifiers
| Name | Olaparib |
| Synonyms | AZD2281 KU 59436 Olaparib Olaparid AZD2281 AZD2281(olaparib) 4-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one 1-(Cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)Methyl]-2-fluorobenzoyl]piperazin 4-[[3-[[4-(Cyclopropylcarbonyl)-1-piperazinyl]carbonyl]-4-fluorophenyl]Methyl]-1(2H)-phthalazinone |
| CAS | 763113-22-0 937799-91-0 |
| EINECS | 642-941-5 |
| 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) |
KU 59436 - Physico-chemical Properties
| Molecular Formula | C24H23FN4O3 |
| Molar Mass | 434.46 |
| Density | 1.43 |
| Solubility | Soluble in DMSO (33 mg/mL), ethanol (1.7 mg/mL), and water (<1 mg/mL) at 25°C. |
| Appearance | solid |
| Color | Off-white |
| pKa | 12.07±0.40(Predicted) |
| Storage Condition | -20°C |
| Stability | 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. |
| Refractive Index | 1.702 |
| Use | A potent inhibitor of PARP |
KU 59436 - Risk and Safety
| Risk Codes | R22 - Harmful if swallowed R38 - Irritating to the skin R37 - Irritating to the respiratory system R36 - Irritating to the eyes |
| Safety Description | S24/25 - Avoid contact with skin and eyes. S37/39 - Wear suitable gloves and eye/face protection |
| HS Code | 29339900 |
| Hazard Class | IRRITANT |
KU 59436 - Introduction
Olaparib (AZD2281, Ku-0059436) is a selective PARP1/2 inhibitor with IC50 of 5 nM/1 nM, which is 300 times stronger than that of Tankyrase-1.
Last Update：2022-10-16 17:28:29
KU 59436 - Reference Information
| ovarian cancer treatment drugs | breast cancer and ovarian cancer are serious public health problems that seriously threaten female students. in recent years, the growth rate of breast cancer incidence in China is 1-2 percentage points higher than that in high-incidence countries. On the other hand, ovarian cancer is still the most severe challenge faced by gynecological oncologists. The reason is that it has no mature early diagnosis method. At the time of diagnosis, about 70% is advanced. Even if complete remission is achieved after effective treatment, there will still be 70% patients. Recurrence, the 5-year survival rate has been hovering around 30-40%. Therefore, people try to establish tertiary prevention and control measures for ovarian cancer like other chronic diseases. A new treatment for ovarian cancer is urgently needed because platinum-based chemotherapy has a limited cycle of use before side effects can be tolerated. Olaparib and other PARP inhibitors under development are oral preparations and are better tolerated, so these drugs can be used for a longer period of time compared with traditional chemotherapy. Olaparib can block an enzyme involved in cell repair and is suitable for patients with certain genetic mutations. This drug also has good prospects for treating other cancers, which opens up a considerable market opportunity for olaparib. On December 19, 2014, the US FDA approved the new anti-cancer drug olaparib olaparib(Lynparza) as a single drug for advanced ovarian cancer patients who have undergone at least 3 chemotherapy before treatment, or for advanced ovarian cancer suspected of BRCA mutation. At the same time, FDA has approved a quantitative and classified diagnostic kit for detecting BRCA1 and BRCA2 gene mutations, BRACAnalysis CDx. Olaparib(Lynparza) is the first PARP inhibitor approved by FDA for listing. On February 2, 2015, the European Food and Drug Administration (EMA) also approved the listing of Olaparib in 28 EU countries including Iceland, Liechtenstein and Norway. However, the indication approved by EMA is slightly different from FDA. The former is for BRCA gene mutation, and the maintenance treatment for patients with advanced epithelial ovarian cancer who have received chemotherapy containing platinum drugs and show response and recurrence before. Figure 1 shows AstraZeneca's anti-cancer drug Lynparza(olaparib) olaparib capsules. |
| pharmacological effects | olaparib is a brand new oral polyadenosine diphosphate ribose polymerase [PARP] Inhibitor, PARP includes the most important members of the three protein families: PARP1, PARP2 and PARP3. PARP enzymes are involved in normal cell homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib in vitro test results show that monotherapy or platinum-based chemotherapy after treatment shows that it inhibits the growth of selected tumor cell lines and reduces the tumor growth of human cancer mouse xenograft model. Treatment with olaparib increased cytotoxicity and antitumor activity in murine tumor model cell lines with ovarian cancer BRCA deficiency. In vitro experimental studies have also shown that the cytotoxicity induced by olaparib may be related to the inhibition of PARP enzyme activity and the increase of PARP-DNA complex formation, resulting in the destruction of cell dynamic balance and cell death. Olaparib is a novel poly-ADP-ribose polymerase (PARP) inhibitor, including PARP1,PARP2, and PARP3. PARP mediates a DNA repair mechanism and plays an important role in DNA damage repair and apoptosis. Therefore, Olaparib specifically acts on the DNA damage repair mechanism of targeted cells, by attacking BRCA1 and BRCA2 mutations The key loopholes in cancer cells play a role and can be used for maintenance treatment of patients with recurrent severe ovarian cancer who have breast cancer susceptibility gene (BRCA) mutations and are sensitive to platinum-based drugs. A study by scientists at the Dana-Farber Cancer Institute at Harvard Medical School in the United States has found that the site of action of olaparib is polymerase Q(POLQ, also known as POLθ). These scientists found that a large number of ovarian cancer patients with homologous recombination (homologous recombination,HR) repair pathway genes are defective, and the protein expression of POLQ is greatly up-regulated. HR is an important repair pathway for repairing DNA chain breaks. They speculate that POLQ is to make up for the lack of HR and participate in DNA repair. experiments show that knocking out POLQ will significantly increase HR activity in cells with normal HR. However, knocking out POLQ will lead to cell death in cells with HR deletion. POLQ contains a RAD51-binding membrane that blocks RAD51-mediated DNA repair. The relevant research results were published in Nature on February 12, 2015. Raphael Ceccaldi is the first author of the research results. studies have revealed that about 10% of ovarian cancer patients and 5% of breast cancer patients carry BRCA1 or BRCA2 gene mutations. BRCA1 and BRCA2 are tumor suppressor genes and are the main components of HR repair pathway. their mutations mean the lack of HR repair pathway. In cancer models with BRCA1 or BRCA2 mutations, PARP, an important component of blocking and repairing single-stranded DNA breaks, can synthesize and kill mutant cancer cells. Crossing BRCA-deficient mice with POLQ-deficient mice resulted in embryo death shortly after gestation, which means that the presence of both repair defects is embryogenic. The above findings indicate that Olaparib, a new oral PARP inhibitor that can kill BRCA-deficient cells, may become a cancer treatment drug for such mutation carriers. Previously, people's understanding of BRCA mutations has not yet had an impact on the treatment options for ovarian cancer or breast cancer. After this study, it means that olaparib can be used for targeted therapy for tumor patients with BRCA1 or BRCA2 gene mutations. The therapeutic target is the genetic defect of cancer cells rather than the target organ. in ovarian and breast cancer cells, BRCA mutation is the first blow to cell survival because it increases their susceptibility to DNA damage. By targeting the backup repair pathway controlled by PARP, olaparib and similar drugs have achieved the second major blow to the continued survival of cells. With the imbalance of the two repair signaling pathways, the accumulation of DNA damage has produced a third major blow to the cell. |
| pharmacokinetics | absorption olaparib is rapidly absorbed after oral administration of capsule preparation with peak plasma concentration is typically realized in 1 to 3 hours after administration. With multiple dosages, there is no obvious savings (savings ratio 1.4-1.5 versus 2 times a day), and steady-state exposure is achieved within 3 to 4 days. limited data suggest that the increase in systemic exposure (AUC) of olaparib is lower than the positive proportion across the dose range of 100 to 400 mg, but the PK data across the test is variable. Co-administration with a high-fat meal showed absorption rate (Tmax delayed by 2 hours), but did not significantly change the degree of olaparib absorption (mean AUC increased by about 20%). Distribution Olaparib has a mean (± standard deviation) apparent distribution volume 167±196 L at steady state after a single 400mg dose of Olaparib. The in vitro protein binding of olaparib is about 82% after plasma concentration is achieved at 400mg twice a day. Metabolism In vitro, CYP3A4 is shown to be the enzyme mainly responsible for the metabolism of olaparib. After oral administration of 14C-olaparib to female patients, olaparib accounts for the majority of circulating radioactivity in plasma (70%). It is widely metabolized in urine and feces without change. Drug radioactivity accounts for 15% and 6% respectively. Metabolism is mostly attributed to the oxidation reaction and the production of some components for subsequent glucuronic acid or sulfuric acid binding. After excretion a single 400 mg dose of olaparib, a mean (standard deviation) terminal plasma half-life of 11.9±4.8 hours and apparent plasma clearance rate of 8.6±7.1L/h were observed. after a single dose of 14C-olaparib, the radioactivity given 86% during the 7-day collection period is recovered, 44% through urine and 42% through feces. Most of the material is excreted as a metabolite. according to the preliminary data from the special renal damage test, when olaparib is given to patients with mild renal damage (CLcr = 50-80 mL/min; N = 14) compared with patients with normal renal function (CLcr >80 mL/min; N = 8) the mean AUC and Cmax of olaparib increased by 1.5 and 1.2-times respectively. No data were available in patients with CLcr < 50 mL/min or in patients on dialysis. |
| drug interaction | In vitro, olaparib is an inhibitor of CYP3A4 and the higher concentration achieved clinically is an inducer of CYP2B6. Olaparib has little non-inhibitory effect on other CYP isoenzymes. In vitro studies have shown that olaparib is the substrate of CYP3A4. according to data from a drug-interaction test (N = 57), when olaparib is given in combination with itraconazole, a strong CYP3A inhibitor, AUC and Cmax of olaparib increase by 2.7-and 1.4-times, respectively. Simulations based on physiological pharmacokinetic (PBPK) models suggest that a moderate CYP3A inhibitor (fluconazole) can increase AUC and Cmax of olaparib by 2-and 1.1-times, respectively. according to data from a drug-interaction test (N = 22), when olaparib is given in combination with rifampicin, a strong CYP3A inducer, AUC and Cmax of olaparib are reduced 87% and 71% respectively. PBPK model simulation suggests that a moderate CYP3A inducer (efavirenz) may reduce AUC and Cmax of olaparib by 50-60% and 20-30% respectively. in vitro studies have shown that olaparib is a P-gp substrate and inhibitor of BCRP,OATP1B1,OCT1,OCT2,OAT3,MATE1 and MATE2K. the clinical relevance of these findings is unknown. (2015-08-22). |
| adverse reactions | (1) the most common adverse reactions (≥ 20%) in clinical trials are anemia, nausea, fatigue (including fatigue), vomiting, diarrhea, taste disorder, dyspepsia, 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%) are increased creatinine, increased mean red blood cell volume, decreased hemoglobin, decreased lymphocytes, decreased absolute neutrophil count, and decreased platelets. |
Last Update：2024-04-09 21:04:16
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KU 59436
296882-82-1
2-酮基-D-葡萄糖酸
6-[4-(difluoromethoxy)phenyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
77-01-0
Poly(oxy-1,2-ethanediyl), .alpha.-(2-methyl-1-oxo-2-propenyl)-.omega.-hydroxy-, C18-22-alkyl ethers
Titanium tris(dodecylbenzenesulfonate)isopropoxide
(PIPERIDIN-4-YLOXY)-ACETIC ACID METHYL ESTER HYDROCHLORIDE
296882-82-1
2-酮基-D-葡萄糖酸
6-[4-(difluoromethoxy)phenyl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
77-01-0
Poly(oxy-1,2-ethanediyl), .alpha.-(2-methyl-1-oxo-2-propenyl)-.omega.-hydroxy-, C18-22-alkyl ethers
Titanium tris(dodecylbenzenesulfonate)isopropoxide
(PIPERIDIN-4-YLOXY)-ACETIC ACID METHYL ESTER HYDROCHLORIDE