Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

Latif, Muhammad; Ashraf, Zaman; Basit, Sulman; Ghaffar, Abdul; Zafar, Muhammad Sohail; Saeed, Aamer; Meo, Sultan Ayoub

doi:10.1039/c8ra01934g

Cited by 5 publications

(1 citation statement)

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“…Still, the acquired resistance to crizotinib—particularly observed in the central nervous system, which remains the most common site of relapse—remains a major problem. Searching for new active compounds led to the discovery of numerous next-generation ALK inhibitors, and surprisingly, most of them are 2,4-diarylaminopyrimidine analogs (named DAAPalogues) [ 74 ]. Among these compounds, there are also some heterocyclic β 2,3 -amino acid derivatives; CEP-28122 mesylate salt, CEP-37440 (and its analogs) and NVP-TAE226 are some examples of ALK inhibitors ( Figure 4 , Compound 33 ).…”

Section: Biological Activitymentioning

confidence: 99%

Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective

Bąchor¹,

Mączyński²

2021

Molecules

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Heterocyclic moieties, especially five and six-membered rings containing nitrogen, oxygen or sulfur atoms, are broadly distributed in nature. Among them, synthetic and natural alike are pharmacologically active compounds and have always been at the forefront of attention due to their pharmacological properties. Heterocycles can be divided into different groups based on the presence of characteristic structural motifs. The presence of β-amino acid and heterocyclic core in one compound is very interesting; additionally, it very often plays a vital role in their biological activity. Usually, such compounds are not considered to be chemicals containing a β-amino acid motif; however, considering them as this class of compounds may open new routes of their preparation and application as new drug precursors or even drugs. The possibility of their application as nonproteinogenic amino acid residues in peptide or peptide derivatives synthesis to prepare a new class of compounds is also promising. This review highlights the actual state of knowledge about β-amino acid moiety-containing heterocycles presenting antiviral, anti-inflammatory, antibacterial compounds, anaplastic lymphoma kinase (ALK) inhibitors, as well as agonist and antagonists of the receptors.

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Section: Biological Activitymentioning

confidence: 99%

Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective

Bąchor¹,

Mączyński²

2021

Molecules

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Design, Synthesis and Biological Evaluation of 2‐(naphthoyl) iminothiazolidin‐4‐ones as Potential Anticancer Agents

et al. 2020

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A library of novel naphthyl bearing 2-iminothiazolidin-4-ones (2-ITZDs) (2 a-2 q) was designed and synthesized through a facile route involving regioselective heterocyclization of unsymmetrical thioureas (1 a-1 q). The synthesis was achieved at ambient temperature in good to excellent yields under catalyst free conditions. The molecular structures of 2-ITZDs were elucidated by spectroscopic techniques such as FT-IR, 1 H-NMR and 13 C-NMR. X-ray structural data was used to establish the structure (2 o) unequivocally and to define the geometry of exo double bond. The in vitro anticancer activity of 2-ITZDs (2 a-2 q) was investigated in several human cancer cell lines (A549, LNCap, PC-3, MDA-MB-231, BxPC3, MIA PaCa2). All compounds showed cytotoxicity with IC 50 values ranging from 6-23 μM in the tested cancer cell lines except MDA-MB-231. Compound 2 k (IC 50 = 7 μM) and the homologous analog 2 q (IC 50 = 6 μM) were found to be equipotent to 2 k and showed moderate cytotoxicity against human breast cell line (DA-MB-231). Furthermore, compound 2 k exhibited a medium permeability, enough metabolic stability and no significant inhibition of hERG channel. Compound 2 k inhibited cytochrome P450 activity below 50 % in 1 A2, 3 A4 and 2 C19, but not in 2 C9 and 2D6 at 10 μM. Structure-activity relationships (SAR) provided useful insights towards this class of compounds and tiled a way to design novel analogues with increased potency.[a] S.

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Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors

Xing

Jing

Zhang

et al. 2018

Bioorganic Chemistry

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Latest perspectives of orally bioavailable 2,4-diarylaminopyrimidine analogues (DAAPalogues) as anaplastic lymphoma kinase inhibitors: discovery and clinical developments

Abstract: This review describes hit-to-drug evolution milestones, synthetic strategies and clinical significance of novel DAAPalogues discovered for ALK inhibition which are either progressing as investigational or preclinical candidates to treat the patients with ALK+-NSCLC.

Cited by 5 publications

References 167 publications

Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective

Selected β2-, β3- and β2,3-Amino Acid Heterocyclic Derivatives and Their Biological Perspective

Design, Synthesis and Biological Evaluation of 2‐(naphthoyl) iminothiazolidin‐4‐ones as Potential Anticancer Agents

Design, synthesis and biological evaluation N2-(2-alkyoxy-6-aliphatic aminopyridin-3-yl)-2,4-diaminepyrimidine derivatives bearing acylamino or DBTD ‘head’ as potential ALK inhibitors

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