Directly targets wild-type and mutant c-Abl kinase domains
A concise and efficient route was
developed for the synthesis of dasatinib. Reaction of
2-chlorothioa-zole (18) with n-butyllithium at low temperature
followed by addition of 2-chloro-6-methylphenyl isocyanate
(19) gave anilide 20 in 86% yield. The amide 20 was
protected as corresponding 4-methoxy benzyl (PMB) anilide
22 in 95% yield which was subsequently reacted with 4-
amino-6-chloro-2-methylpyrimidine (23) in the presence of
sodium hydride in hot THF to give compound 24 in 83%
yield. The PMB protecting group was then removed with
triflic acid to give compound 25 in 99% yield. Compound 25
was reacted with 1-(2-hydroxyethyl)piperazine (26) in refluxing
dioxane to give dasatinib (III) in 91% yield.
Dasatinib, developed and marketed by Bristol Myers, is
the first approved oral tyrosine kinase inhibitor which binds
to multiple conformations of ABL kinase for the treatment of
two leukemia indications: chronic myeloid leukemia (CML)
and Philadelphia chromosome-positive acute lymphoblastic
leukemia (Ph+ ALL). Dasatinib is a highly potent, ATPcompetitive ATPcompetitive
kinase inhibitor which, at nanomolar concentrations,
inhibits BCR-ABL, SRC family, c-KIT, EPHA2 and
Suitable for treatment of chronic myeloid leukemia which is resistant or intolerant to the treating programs including imatinib mesylate.
A new, oral, small-molecule Tyrosine Kinase Inhibitor (TKI) for the treatment of CML. Antineoplastic
Dasatinib is an oral potent oncogenic kinase inhibitor, which can block signal of cancer cell replication acceleration , in May 2009, the US Food and Drug Administration (FDA) formally approved the sale of dasatinib , It has been clinically used for the treatment of various chronic myeloid leukemia (CML), including treatment of chronic myeloid leukemia which is resistant or intolerant to the treating programs including imatinib mesylate., Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) and the treatment of patients with solid tumors.
October 28, 2010 ,the FDA approved dasatinib (Sprycel) of the new indication which is used for the treatment of the rare leukemia first diagnosed Philadelphia chromosome-positive called chronic myeloid leukemia (Ph + CP-CML) . The disease is a blood and bone marrow disease associated with genetic abnormality .
An open-label randomized clinical trial conducted in patients with CP-CML evaluated the safety and efficacy of dasatinib . Common side effects include decreased activity of the bone marrow caused by red blood cells, white blood cells and platelets decreased (myelosuppression), fluid retention, diarrhea, headache, musculoskeletal pain, and rash.
October 11, 2011, the US Food and Drug Administration (FDA) said the leukemia drug dasatinib (Sprycel, Bristol-Myers Squibb Company) might increase pulmonary arterial hypertension (PAH) risk. Pulmonary hypertension is a rare but serious disease that can lead to the condition that heart pumping blood to the lungs becomes more difficult by raising the pressure . PAH symptoms include shortness of breath, fatigue, swelling of the legs and ankles, clinicians must differentiate these symptoms from other similar symptoms.
Since 2006 Dasatinib was approved in the US market ,there had been 12 associated pulmonary hypertension events ,pulmonary hypertension symptoms included shortness of breath, fatigue, hypoxia and fluid retention, patients then were confirmed pulmonary hypertension by the results of right heart catheterization ,studies have shown that the biggest cause of the disease may come from patients taking dasatinib.
The above information is edited by the Chemicalbook of Tian Ye.
Dasatinib is a novel, potent and multi-targeted inhibitor that targets Abl, Src and c-Kit, with IC50 of ＜1 nM, 0.8 nM and 79 nM, respectively.
Dasatinib is available in 20-, 50-, and 70-mg tablets fororal administration in the treatment of CML and ALL thatare Ph1 positive. Although dasatinib is more potent thanimatinib, bioavailability is much lower with values rangingbetween 14% to 34%. The agent is extensively metabolizedwith as many as 29 metabolites seen as result of oxidationby primarily CYP3A4 and phase II conjugation.The agent may act as an inhibitor of CYP3A4 andCYP2C8. Metabolism does give an active metabolite, but this accounts for only 5% of the total and is not believed tobe important for the overall activity of the agent. Dasatinibis 95% protein bound with a terminal half-life of 3 to5 hours. The majority of the drug and metabolites are eliminatedin the feces. The most common side effects are skinrash, nausea, diarrhea, and fatigue. Serious side effects includemyelosuppression appearing as neutropenia andthrombocytopenia, bleeding of the brain and GI tract, andfluid retention.
Sprycel (Bristol-Myers Squibb).
Bristol–Myers Squibb (US)