説明
Lapatinib, a new member of the 4-anilinoquinazoline class of RTK inhibitors
(RTKIs), was launched as an oral treatment for breast cancer.
Lapatinib has dual affinity for EGFR and HER2 tyrosine kinases. It is indicated
in combination with capecitabine for treating patients with advanced or
metastatic breast cancer whose tumors overexpress HER2 and who have
received prior therapy including an anthracycline, a taxane, and trastuzumab.
Previously marketed drugs from the 4-anilinoquinazoline class include
erlotinib (Tarceva) and gefitinib (IressaTM), both of which are indicated for
treating non-small-cell lung cancer (NSCLC). As with erlotinib and gefitinib, To Market, To Market 2007 475 lapatinib is an ATP-competitive kinase inhibitor. It inhibits the tyrosine kinase activity EGFR and HER-2 with apparent Ki values of 3 and 13 nM, respectively, and has slow off-rate kinetics (t1/2X300 min).
In addition, dividing the daily dose of lapatinib results in approximately 2-fold higher exposure at steady state compared to the same total dose administered once daily.
The chemical synthesis of lapatinib entails the condensation of 4-chloro-6-iodoquinazoline and 3-chloro-4-(3-fluorobenzyloxy)aniline to produce a diaryl amine intermediate followed by Stille coupling of the iodo group with 5-dioxolanyl-2-(tributylstannyl)furan and subsequent acid hydrolysis of the cyclic ketal to the corresponding aldehyde. Finally, reductive amination of the aldehyde intermediate with 2-(methanesulfonyl) ethylamine in the presence of sodium triacetoxyborohydride produces lapatinib.
.
