Description
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 PDGFR-B.
Originator
Bristol–Myers Squibb (US)
Brand name
Sprycel (Bristol-Myers Squibb).
General Description
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.
Synthesis
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.
Metabolism
Dasatinib is extensively metabolised, mainly via the
cytochrome P450 isoenzyme CYP3A4, forming an active
metabolite.
Elimination is predominantly in the faeces, mostly as
metabolites. Following a single oral dose of [14C]-labelled
dasatinib, approximately 89% of the dose was eliminated
within 10 days, with 4% and 85% of the radioactivity
recovered in the urine and faeces, respectively. Unchanged
dasatinib accounted for 0.1% and 19% of the dose in
urine and faeces, respectively, with the remainder of the
dose as metabolites.
References
1) Lombardo et al. (2004), Discovery of N-2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a duel Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays; J. Med. Chem., 47 6658
2) Nam et al. (2005), Action of the Src family kinase inhibitor dasatinib (BMS-354825), on human prostate cancer cells; Cancer Res., 65 9185
3) Johnson et al. (2005), Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells; Clin. Cancer Res., 11 6924
