Discovery of &lt;i&gt;N&lt;/i&gt;-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-&lt;i&gt;N&lt;/i&gt;′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor

Iikubo, Kazuhiko; Kondoh, Yutaka; Shimada, Ichio; Matsuya, Takahiro; Mori, Kenichi; Ueno, Yoshio; Okada, Minoru

doi:10.1248/cpb.c17-00784

Cited by 15 publications

(16 citation statements)

References 17 publications

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“…The moderate yields were consistent with those previously obtained in the literature for similar transformations. 19 Further analogues of 19 without the additional chlorine atom were prepared from dichlorotriazine (23) by sequential nucleophilic aromatic substitution with leucine tert-butyl ester and substituted phenylenediamine subunits to afford 25−26 in moderate yields using the methods previously described (Scheme 2). Yields compared favorably to similar transformations in the literature, which show significant variance, particularly for the second substitution step (from 5 to >95%), although sulfoxide and sulfonamide derivatives were typically associated with lower yields.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

et al. 2022

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C-type natriuretic peptide (CNP) is involved in the regulation of vascular homeostasis, which is at least partly mediated through agonism of natriuretic peptide receptor C (NPR-C), and loss of this signaling has been associated with vascular dysfunction. As such, NPR-C is a novel therapeutic target to treat cardiovascular diseases. A series of novel small molecules have been designed and synthesized, and their structure−activity relationships were evaluated by a surface plasmon resonance binding assay. The biological activity of hit compounds was confirmed through organ bath assays measuring vascular relaxation and inhibition of cAMP production, which was shown to be linked to its NPR-C activity. Lead compound 1 was identified as a potent agonist (EC 50 ∼ 1 μM) with promising in vivo pharmacokinetic properties.

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Section: ■ Results and Discussionmentioning

confidence: 99%

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

et al. 2022

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“…ASP3026, a recently developed anaplastic lymphoma kinase (ALK) inhibitor ( 38 ), is among the lead hits (Figure 1A ). ASP3026 contains an ( N 2 , N 4 -diphenyl-1,3,5-triazine-2,4-diamine, Ph-Az-Ph) core structure, an isopropylsulfonyl- substituent on the first phenyl moiety, and 2-methoxy-4-(4-methylpiperazinyl)piperidinyl- substituents on the second phenyl moiety (Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Inhibition ofPlasmodium falciparumLysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

Zhou

Huang

Zheng

et al. 2020

Nucleic Acids Research

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Aminoacyl-tRNA synthetases are attractive targets for the development of antibacterial, antifungal, antiparasitic agents and for the treatment of other human diseases. Lysyl-tRNA synthetase (LysRS) from this family has been validated as a promising target for the development of antimalarial drugs. Here, we developed a high-throughput compatible assay and screened 1215 bioactive compounds to identify Plasmodium falciparum cytoplasmic LysRS (PfLysRS) inhibitor. ASP3026, an anaplastic lymphoma kinase inhibitor that was used in clinical trials for the treatment of B-cell lymphoma and solid tumors, was identified as a novel PfLysRS inhibitor. ASP3026 suppresses the enzymatic activity of PfLysRS at nanomolar potency, which is >380-fold more effective than inhibition of the human counterpart. In addition, the compound suppressed blood-stage P. falciparum growth. To understand the molecular mechanism of inhibition by ASP3026, we further solved the cocrystal structure of PfLysRS-ASP3026 at a resolution of 2.49 Å, providing clues for further optimization of the compound. Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.

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“…However, compound 7 (the maximum α7 current activation is approximately 210%) showed no obvious enhancement of α7 currents expressed in Xenopus oocytes in two-electrode voltage clamp (TEVC) recordings. Literature results indicate that 1,3,5-triazine is a privileged motif and is commonly used in drug candidates with various activities, including potential anticancer activities, antiviral activities, analgesic and anti-inflammatory activity, and antiparasitic activities, for treating neurological disorders and ion-channel-related diseases . We, therefore, introduced 1,3,5-triazin-2-amine instead of 4-amino-pyrimidine in compound 7 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

et al. 2021

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Enhancing neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) function can alleviate cognitive deficits. Here, we report the design, synthesis, and evaluation of N-(4-(trifluoromethoxy)phenyl)-1,3,5-triazin-2-amine derivatives 8−10 as a series of novel α7 nAChR positive allosteric modulators (PAMs). The representative compound 10e functions as a type I PAM with an EC 50 of 3.0 μM and approximately 38-fold enhancement of α7 current in the presence of agonist acetylcholine (100 μM). It specifically enhances α7 current with high selectivity. Compound 10e shows good pharmacokinetic property in mice. Intraperitoneal injection of 10e (3 mg/kg) exhibits sufficient blood−brain barrier penetration in mice. Furthermore, 10e can also rescue the auditory gating deficit in mice with schizophrenia-like behavior. Molecular docking of 10e with homopentameric α7 nAChR reveals a new mode of action. These results support the potential of 10e for treatment for schizophrenia and Alzheimer's disease.

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Discovery of <i>N</i>-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-<i>N</i>′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor

Cited by 15 publications

References 17 publications

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

A Series of Substituted Bis-Aminotriazines Are Activators of the Natriuretic Peptide Receptor C

Inhibition ofPlasmodium falciparumLysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor

Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

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