ABT-199

Bezeichnung:ABT-199

CAS-Nr1257044-40-8

Englisch Name:ABT-199

CBNumberCB62645962

SummenformelC45H50ClN7O7S

Molgewicht868.44

MOL-Datei1257044-40-8.mol

ABT-199 physikalisch-chemischer Eigenschaften

Schmelzpunkt	>150°C (dec.)
Dichte	1.340±0.06 g/cm3(Predicted)
storage temp.	-20°C Freezer
Löslichkeit	DMSO (Slightly)
Aggregatzustand	Yellow solid.
pka	4.09±0.10(Predicted)
Farbe	Light Yellow to Yellow

Gefahreninformationscode (GHS)

ABT-199 Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
Venetoclax, codeveloped by AbbVie (previously Abbott Laboratories) and Genentech/ Roche, was approved in the US for treatment of patients with chronic lymphocytic leukemia (CLL). To meet qualifications for venetoclax treatment, patients must have received prior therapy and possess the 17p deletion genetic mutation, as determined by USFDA testing. Venetoclax functions as a selective inhibitor of B cell lymphoma subtype 2 (BCL-2), which is often overexpressed on malignant cells and thus leads to impairment of the apoptotic pathway. Along these lines, the orally dosed small molecule drug restores the ability of malignant cells to undergo apoptosis as its mechanism of action.90 Although other BCL-2 inhibitors are known, development of similar agents such as navitoclox have been pursued and halted due to undesired inhibition of BCL-XL, leading to significant thrombocytopenia and demonstrating the need for more selective inhibitors. Venetoclax is also currently being considered for approval in Europe and Canada for similar indications and is in various stages of development for the treatment of non-Hodgkin lymphomas (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), and several other disorders, either as a combination therapy or a stand-alone treatment.
Verwenden
ABT 199 (>99%) is a potent and selective BCL-2 inhibitor that achieves potent antitumour activity while sparing platelets. It’s practical application is to treat chronic lymphocytic leukaemic cells and estrogen receptor-positive breast cancer.
Definition
ChEBI: A member of the class of pyrrolopyridines that is a potent inhibitor of the antiapoptotic protein B-cell lymphoma 2. It is used for treamtment of chronic lymphocytic leukemia with 17p deletion.
Clinical Use
Selective inhibitor of B-cell lymphoma protein:
Treatment of chronic lymphocytic leukaemia
Synthese
The manufacturing route to venetoclax takes place by coupling of three key structural subunits: azaindole 162, sulfonamide 165, and piperazine 172. The first of these subunits was generated in two steps from commercially available 4-bromo-2-fluoro-1-iodo-benzene (159). Grignard formation of iodide 159 (i-PrMgCl) followed by quenching with Boc2O provided the desired tert-butyl ester 160 without the need for chromatographic purification. Aromatic substitution of crude 160 with azaindole 161 provided access to 162 in 86% yield after recrystallization from EtOAc/heptane. Sulfonamide 165 was formed in 91% yield and 99.9% purity via aromatic substitution of commercially available 163 with amine 164 at 80 ??C (DIPEA, MeCN).

Synthesis of the third venetoclax subunit, piperazine amine hydrochloride salt 172, began with commercial cyclohexanone 166. Vilsmeier-Haack formylation of the sterically more accessible enol tautomer of 166 delivered vinyl chloride 167 in quantitative yield. Coupling of this chloride with commercial aryl boronate 168 gave rise to transient enal 169 in 87% assay yield, which was not isolated. Crude 169 was then carried into a reductive amination reaction with commercial N-Boc piperazine (170). Precipitation and recrystallization from acetonitrile ultimately furnished piperazinyl alkene 171 in 74% yield from 167. Finally, subunit 172 was obtained via Boc removal with concentrated HCl in IPA at 65 ??C and subsequent filtration, conditions that provided a 95% yield of high purity intermediate 172 (>99.5%).

The final approach to venetoclax involved a palladiumcatalyzed coupling of amine 172 with aryl bromide 162, ester hydrolysis, and coupling of the resulting carboxylic acid with sulfonamide 165. In practice, Buchwald-Hartwig amination of 162 with 172 proceeded smoothly and relied upon workup with cysteine to enable cleansing of residual palladium from the reaction mixture. This reaction gave rise to advanced intermediate 173 in 89% yield after crystallization from cyclohexane. Treatment of 173 with t- BuOK/H2O/2-MeTHF at 55 ??C provided the corresponding free acid, which was immediately activated with EDC/DMAP/ Et3N to promote coupling with sulfonamide 165 at room temperature. The final drug target could be accessed by crystallization from EtOAc and washing with 1:1 DCM/EtOAc, yielding venetoclax (XVIII) in free base form in 71% over the two final steps. This synthetic route was capable of fashioning the drug target in 52% overall yield based on the longest linear sequence (7 steps).
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - reduce venetoclax dose; avoid with rifampicin.
Anticoagulants: avoid with dabigatran; concentration of warfarin increased.
Antidepressants: avoid with St John’s wort.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid.
Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - reduce venetoclax dose.
Antipsychotics: increased risk of agranulocytosis with clozapine - avoid.
Antivirals: concentration possibly reduced by efavirenz and etravirine - avoid; concentration possibly increased by ritonavir - reduce venetoclax dose.
Bosentan: concentration of venetoclax possibly reduced by bosentan - avoid.
Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - reduce venetoclax dose.
Cardiac glycosides: avoid with digoxin.
Cytotoxics: avoid with everolimus.
Grapefruit juice: avoid concomitant use.
Modafinil: concentration of venetoclax possibly reduced - avoid.
Sirolimus: avoid concomitant use.
Vaccines: avoid with live vaccines.
Stoffwechsel
In vitro studies show that venetoclax is mainly metabolised by cytochrome P450 CYP3A4. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro.
Excretion is mainly by the faecal route (>99.9
%; 20.8
% unchanged).
Lager
Store at -20°C

ABT-199 Upstream-Materialien And Downstream Produkte

ABT-199 Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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