Osimertinib
[N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide]
is an oral, small molecule, irreversible and mutant-selective inhibitor of epidermal
growth factor receptor (EGFR) kinase activity. Chemically, Osimertinib is a
mono-anilino-pyrimidine compound that is structurally and pharmacologically
distinct from all other third-generation tyrosine kinase inhibitors (TKIs)
including CO-1686 and WZ4002 [1, 2].
Osimertinib is designed in such a manner that it irreversibly and selectively targets both sensitizing and resistant-T790M mutant EGFR whilst harboring less activity towards wild-type EGFR. Osimertinib has been developed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR.
Osimertinib was granted US FDA breakthrough therapy designation, orphan drug status and fast track status for non-small cell lung cancer (NSCLC) in 2014, and was granted US FDA priority review designation by early September 2015. In May 2015, Osimertinib was granted accelerated assessment status in the same indication in the EU, and received priority review status in Japan in the third quarter of 2015.
Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy [1].
J Med Chem 2014, 57(20), 8249-8267: It is one of the earliest reported synthetic route for Osimertinib. The article details the design, discovery and activity of Osimertinib and its various analogues.
Starting Material (Route 1):
Route 2: Shorter with better yields too !!!
Final Synthesis:
Identifications:
Experimental: 1H NMR (400 MHz, DMSO, 22 °C) δ 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.2-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s).
References:
1. Greig, S. L. Osimertinib: First Global Approval. Drugs 2016, 76(2), 263-73. (FMO only)
2. Finlay, M. R.; et. al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014, 57(20), 8249-67. (FMO only)
 |
| Osimertinib: 2D and 3D Structure |
Osimertinib is designed in such a manner that it irreversibly and selectively targets both sensitizing and resistant-T790M mutant EGFR whilst harboring less activity towards wild-type EGFR. Osimertinib has been developed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR.
Osimertinib was granted US FDA breakthrough therapy designation, orphan drug status and fast track status for non-small cell lung cancer (NSCLC) in 2014, and was granted US FDA priority review designation by early September 2015. In May 2015, Osimertinib was granted accelerated assessment status in the same indication in the EU, and received priority review status in Japan in the third quarter of 2015.
Osimertinib has been designed to target the EGFR T790M mutation that is often present in NSCLC patients with acquired EGFR TKI resistance, while sparing wild-type EGFR. In November 2015, the tablet formulation of osimertinib was granted accelerated approval in the USA for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed on or after EGFR TKI therapy [1].
Dosages
and Approvals:
In Nov
2015, Osimertinib (Tradename: Tagrisso) a third-generation EGFR TKI that
targets tumours with certain EGFR mutations, including T790M,got an accelerated approval from the US FDA for the
treatment of patients with metastatic EGFR T790M mutation-positive NSCLC (as
detected by an FDA-approved test) who have progressed on or after EGFR TKI
therapy.
The
recommended dosage of Osimertinib is 80 mg once daily until unacceptable toxicity
or disease progression (PD). Osimertinib tablets (available as 40 and 80 mg)
can be taken with or without food, or in patients who have difficulty
swallowing solids, dispersed in about 50 mL of noncarbonated water and
immediately consumed or administered via nasogastric tube.
A joint
effort of AstraZeneca and University of Cambridge since 2014 is credited with
discovery of Osimertinib, where the university’s researchers gain access to key
compounds from AstraZeneca’s investigation pipeline, including Osimertinib. In
October 2015, AstraZeneca entered into a collaborative agreement with Eli Lilly
to investigate the use of Osimertinib as combination therapy (with Ramucirumab
or Necitumumab) in patients with solid tumours.
Osimertinib Synthesis
J Med Chem 2014, 57(20), 8249-8267: It is one of the earliest reported synthetic route for Osimertinib. The article details the design, discovery and activity of Osimertinib and its various analogues.
Starting Material (Route 1):
Route 2: Shorter with better yields too !!!
Final Synthesis:
Identifications:
 |
| 1H NMR (Estimated) for Osimertinib |
Experimental: 1H NMR (400 MHz, DMSO, 22 °C) δ 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.2-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s).
 |
| 13C-NMR (Estimated) for Osimertinib |
Experimental:
13C NMR (176 MHz, DMSO, 22 °C) δ 32.8, 42.6, 45.1, 55.7, 56.0, 56.8, 105.3,
107.1, 110.4, 112.4, 113.3, 120.8, 121.2, 121.9, 125.3, 125.5, 125.9, 127.7,
132.4, 133.8, 137.3, 137.7, 145.8, 157.6, 158.9, 159.8, 161.5, 162.3.
Sideeffects: The most common
adverse events (AEs) of any grade with Osimertinib (occurring with greater than
20 % incidence) were diarrhea (47 %), rashes and acne (group term; 40 %),
nausea (22 %), decreased appetite (21 %) and dry skin (20 %). The incidences of
some adverse events, including diarrhoea and rash, increased in a
dose-dependent fashion.
Based on clinical trial data, the US
prescribing information for Osimertinib carries warnings and precautions
regarding the increased risk of ILD/pneumonitis, QTc interval prolongation and
cardiomyopathy during treatment.
Results
from clinical trials reveal that pneumonitis-like events were reported in six
patients (2.4 %), all of whom stopped treatment and had resolved or were
resolving at the time of analysis. Eleven patients (4.3 %) experienced
prolongation of QTc interval and six patients (2.4 %) reported hyperglycaemia
during Osimertinib treatment; none of these patients required dosage reduction
or drug discontinuation. Of the seven fatal adverse events with Osimertinib,
one case of pneumonia was considered to be possibly treatment-related.
1. Greig, S. L. Osimertinib: First Global Approval. Drugs 2016, 76(2), 263-73. (FMO only)
2. Finlay, M. R.; et. al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014, 57(20), 8249-67. (FMO only)
