Erlotinib

The previous synthesis involves use of corrosive chemicals such as thionyl chloride/phosphoryl chloride, costly reagents such as platinum oxide, and flammable gas such as hydrogen at high-temperature reaction conditions. To overcome these issues, an easily scalable, convergent, and versatile process for the preparation of erlotinib was reported in 56% overall yield. Nitro reduction using sodium dithionite in aqueous medium gave aniline 

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Erlotinib (Tarceva ) competes with ATP in the HER1/EGFR ATP-binding pocket. It is used in the clinic in locally advanced or metastatic non-small cell lung cancer after failure of at least one chemotherapy regime [1, 3, 5]. 

Erlotinib (Tarceva) TKI EGFR Inhibition of kinase activity - ATP-competitive NSCLC Pancreatic cancer... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Erlotinib, whose pharmacology is not entirely understood, is believed to inhibit the intracellular phosphorylation of the epidermal growth factor receptor. Erlotonib is about 60% absorbed after oral administration food increases bioavailability to almost 100%. The time to peak concentrations is... 

Docetaxel, pemetrexed, and an oral epidermal growth factor receptor inhibitor, erlotinib, are options for unresectable stage III or IV NSCLC patients with good performance status who progress during or after first-line therapy. 

Erlotinib (Tarceva) EGFR tyrosine kinase inhibitor Refractory non-smaU ceU lung cancer Randomized Phase III... 

The agents approved include Cefitinib (Iressa " ) (AstraZeneca), Imatinib mesylate (Cleevec) (Novartis Pharmaceuticals, East Hanover, NJ, U.S.A.), and Erlotinib (Tarceva ) (Cenentech). 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

Shepherd, F.A. et al., A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Croup (NCIC CTC) trial, Proc. Am. Soc. Clin. Oncol., 22(SuppL), 14S, Abstr. 7022, 2004. 

Pao, W., Miller, V. A., PoUti, K. A., et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73. 

Erlotinib 2004 Non-small cell lung cancer, pancreatic EGFR kinase inhibitor [50]... 

The binding mode of the aminoquinazoline inhibitor, erlotinib, is consistent with that which had been observed previously for the intracellular kinases CDK2 and p38 [29]. The N1 and C8 edge of the heterocycle is oriented toward the hinge, with N1 accepting a hydrogen bond from Met769. N3... 

Fig. 3 Comparison of erlotinib (thin lines) with lapatinib (thick lines). Tbe C-helix is portrayed as a backbone ribbon, and tbe side chain of Met742 is explicitly shown...

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