Description
Sorafenib is a small molecular inhibitor of several kinases involved in tumor
angiogenesis and proliferation, including, but not limited to, Raf (IC50=12nM for
Raf-1), VEGFR (IC50=90nM for VEGFR-2 and IC50=12nM for VEGFR-3),
and platelet derived growth factor receptor (IC50=57nM for PDGFR-b). Specifically,
sorafenib blocks tumor progression by inhibiting cellular proliferation that is
dependent on activation of the MAPK pathway (Raf) and/or inhibiting tumor
angiogenesis through VEGFR and/or PDGFR. While it may be effective in the
treatment of a variety of tumors, the first approvable indication is for renal cell
carcinoma. Overall, the drug appears to be well tolerated by the majority
of patients at the 400 mg b.i.d. continuous dosing. As an inhibitor of multiple
kinases vital for tumor progression, sorafenib may possess wide-spectrum antitumor
properties and may emerge as an effective weapon against a variety of solid
tumors.
Chemical Properties
Light Yellow Solid
Originator
Bayer/Onyx (Germany)
Definition
ChEBI: Sorafenib is a member of the class of phenylureas that is urea in which one of the nitrogens is substituted by a 4-chloro-3-trifluorophenyl group while the other is substituted by a phenyl group which, in turn, is substituted at the para position by a [2-(methylcarbamoyl)pyridin-4-yl]oxy group. It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anticoronaviral agent and a ferroptosis inducer. It is a pyridinecarboxamide, a member of monochlorobenzenes, an aromatic ether, a member of (trifluoromethyl)benzenes and a member of phenylureas.
Brand name
Nexavar (Bayer HealthCare); Xarelto (Bayer HealthCare).
Flammability and Explosibility
Nonflammable
Clinical Use
Protein kinase inhibitor:
Treatment of advanced renal cell carcinoma
Treatment of hepatocellular carcinoma
Treatment of thyroid cancer
Synthesis
An improved, four-step synthesis in 63% overall yield
was published recently and is illustrated in the scheme.
Picolinic acid (127) was heated with Vilsmeier reagent for
16 hr to give 128 in 89% yield as an off-white solid. The
acid chloride 128 was treated with methylamine in methanol
at low temperature to give amide 129 in 88% yield as paleyellow
crystals after its crystallization from ethyl acetate.
4-Aminophenol anion was generated under a basic condition
and compound 129 was added to the anion solution to give
corresponding addition compound 131 in 87% yield. For an
unknown reason, potassium carbonate used in the reaction
increased the reaction rate significantly. Finally, compound
131 was condensed with isocyanate 132 in methylene chloride
to give sorafenib (XVIII) in 92% yield as a white solid.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: may enhance effect of coumarins.
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Antivirals: avoid with boceprevir.
Metabolism
Sorafenib is metabolised primarily in the liver and
undergoes oxidative metabolism mediated by CYP3A4,
as well as glucuronidation mediated by UGT1A9. 8
metabolites have been identified, during in vitro studies
one has been shown to have equal activity to sorafenib.
About 96% of a dose is excreted within 14 days, with
77%, mostly as unchanged drug, recovered in the faeces,
and 19% in the urine as glucuronidated metabolites.
