N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide
[CAS# 1421373-65-0]

Identification

• Classification: Biochemical >> Inhibitor >> Protein tyrosine kinase
• Name: N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide
• Synonyms: osimertinib
• Molecular Formula: C₂₈H₃₃N₇O₂
• Molecular Weight: 499.61
• CAS Registry Number: 1421373-65-0
• SMILES: CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Solubility: 100 mM in water, 75 mM in DMS (Expl.)
• Index of refraction: 1.618 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovery and Applications

N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide is a synthetic small molecule designed for selective inhibition of specific intracellular kinase enzymes. The compound's intricate structure features several pharmacologically relevant functional groups and heterocyclic frameworks that contribute to its biological activity and molecular recognition profile.

The molecular architecture of this compound includes a central phenyl ring substituted at multiple positions, forming the core of the molecule. At the 4-position of the phenyl ring, a methoxy group enhances the lipophilicity and may participate in hydrogen bonding interactions within biological targets. At the 5-position, the phenyl ring is substituted with a [4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino group, which provides a dual heteroaromatic system. This indole-pyrimidine fragment plays a critical role in molecular binding, particularly in mimicking ATP or nucleotide substrates in kinase active sites. The indole ring system often contributes to π-π stacking or hydrophobic interactions, while the pyrimidine moiety can coordinate through hydrogen bonds or act as a hydrogen bond acceptor.

The 2-position of the phenyl ring is linked to a flexible dimethylaminoethylmethylamino chain. This side chain introduces polar, basic functionality into the molecule, enhancing aqueous solubility and contributing to favorable pharmacokinetic characteristics. This moiety is frequently observed in drug design to modulate bioavailability and membrane permeability while offering potential for ionic interactions with acidic residues in enzyme binding pockets.

At the amide terminus of the molecule, the 2-propenamide (acrylamide) group is conjugated through an aniline-type linkage. This functional group is capable of acting as a Michael acceptor, which may impart irreversible binding characteristics to nucleophilic residues, such as cysteines, in target proteins. However, in this specific context, the acrylamide moiety is more likely incorporated to fine-tune conformational rigidity and binding orientation rather than as a reactive warhead, depending on the exact biochemical target.

This compound is structurally related to a class of kinase inhibitors developed for their ability to block aberrant signaling pathways implicated in various cancers. In particular, the combination of a heteroaromatic scaffold with a substituted aniline and an amide tail is characteristic of inhibitors targeting receptor tyrosine kinases such as RET, VEGFR, or EGFR. Such molecules function by occupying the ATP-binding site of the kinase domain, thereby preventing phosphorylation of downstream signaling molecules involved in cell proliferation, migration, and survival.

Compounds of this design are evaluated for their binding affinity and selectivity profiles through enzymatic assays, cell-based experiments, and structural studies such as X-ray crystallography. The presence of the indole and pyrimidine groups enables strong non-covalent interactions with key residues in the kinase active site, contributing to potent inhibition. Medicinal chemistry optimization efforts often focus on enhancing the pharmacodynamic and pharmacokinetic properties, minimizing off-target effects, and improving metabolic stability.

In preclinical studies, compounds of this type may demonstrate efficacy in inhibiting tumor growth in xenograft models or patient-derived cells harboring activating mutations or overexpression of specific kinases. The clinical development of such inhibitors typically follows evaluation of their bioavailability, toxicity profile, and therapeutic index in relevant models.

N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide exemplifies a rationally designed small molecule with a multi-substituted scaffold, tailored to engage with high specificity a target kinase domain and modulate its activity for therapeutic purposes.

References

2017. Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance. Molecular Cancer Therapeutics, 16(11).
DOI: 10.1158/1535-7163.mct-17-0413

2020. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. The Lancet Oncology, 21(3).
DOI: 10.1016/s1470-2045(19)30785-5

2021. Exosome-based detection of EGFR T790M in plasma and pleural fluid of prospectively enrolled non-small cell lung cancer patients after first-line tyrosine kinase inhibitor therapy. Cancer Cell International, 21(1).
DOI: 10.1186/s12935-021-01761-x