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Kinase inhibitor compounds and compositions and methods of use

A technology for compounds, solvates, applied in the field of kinase inhibitor compounds and compositions and uses, which can solve problems such as the potential for drug development that limit therapeutic utility

Pending Publication Date: 2020-12-25
MT SINAI SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Since DYRK1A and NFAT are widely expressed outside of β-cells, it is known that the harmine analog has off-target effects, leading to pharmacological side effects including CNS and anti-tumor activity, thus limiting its therapeutic utility and use in chronic diseases such as diabetes. Potential for disease drug development

Method used

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  • Kinase inhibitor compounds and compositions and methods of use
  • Kinase inhibitor compounds and compositions and methods of use
  • Kinase inhibitor compounds and compositions and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0272] Example 1 - Materials and methods used in Examples 2-5

[0273] 1 H and 13 C NMR spectrum. 1 H and 13 C NMR spectra were performed on a Bruker DRX-600 spectrometer for 1 H at 600MHz and for 13 C obtained at 150MHz. TLC was performed on aluminum plates coated with silica (200 μm in thickness) or aluminum oxide (200 μm in thickness) provided by Sorbent Technologies, and column chromatography was performed on a column equipped with a variable wavelength detector and fractionated Collector's Teledyne ISCO combiflash, using RediSep Rf high-efficiency silica flash column provided by Teledyne ISCO. LCMS analysis was performed on an Agilent Technologies G1969A high resolution API-TOF mass spectrometer connected to an Agilent Technologies 1200HPLC system. Samples were ionized in positive mode by electrospray ionization (ESI). Chromatography was performed on a 2.1×150 mm Zorbax300SB-C18 5-μm column with water containing 0.1% formic acid as solvent A and acetonitrile conta...

Embodiment 2

[0301] Example 2 - Chemical Synthesis of Selected Haraline Analogs

[0302] The 1-position harmine analog according to figure 1 Outlined reaction sequence for synthesis. The classical diazotization of m-anisidine to form the corresponding aryldiazonium salt, coupling of the aryldiazonium salt with 3-carboxy-2-piperidinone yields arylhydrazone 1-2 (Luis et al., "The Fischer Indole Synthesis of 8-Methyl-5-Substituted-1-Oxo-β-Carbolines: ARemarkable High Yield of a[1,2]-Methyl Migration," Tetrahedron 47(9):1737-44(1991), hereby incorporated by reference in its entirety). The resulting arylhydrazone was subjected to Fisher indole cyclization in the presence of formic acid to give 1,2,3,4-tetrahydro-1-oxo-β-carboline 1-3 (Luis et al., "The Fischer Indole Synthesis of 8-Methyl-5-Substituted-1-Oxo-β-Carbolines: A Remarkable High Yield of a[1,2]-Methyl Migration," Tetrahedron 4(9):1737-44( 1991), which is hereby incorporated by reference in its entirety). Oxidation of 1-3 using D...

Embodiment 3

[0305] Example 3 - Structure-Activity Relationship Study (SAR) of Selected Harmine Analogs

[0306] Introduction of structural modifications to the 1-position of harmine to identify novel harmine-based DYRK1A inhibitors that can be linked to GLP-1 agonists for β-cell-targeted delivery. according to Figure 1-2 According to the route described in , a total of 15 kinds of harmine analogs were synthesized. These analogs were initially screened for DYRK1A binding activity at 1000 nM and 300 nM using the FRET-based LanthaScreen binding assay (Life Technologies). Those compounds showing ≥50% inhibition at 300 nM were titrated using ten serial three-fold dilutions (in duplicate) to determine the IC 50 .

[0307] The effect of a cycloalkylamine at the 1-position of hamateline on DYRK1A binding was investigated. First, three analogs having azetidine (1-6a), pyrrolidine (1-6b) and piperidine (1-6c) substituents at the 1-position were synthesized. Compound 1-6a showed the best activ...

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Abstract

Described herein are compounds having the following structure: formula (I) or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof. Also disclosed are compositions containing the compounds, methods of inhibiting activity of DYRKl A in a cell, methods of increasing cell proliferation in a population of pancreatic beta cells, methods of treating a subject for a condition associated with insufficient insulin secretion, and methods of treating a subject for a neurological disorder.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 645,560, filed March 20, 2018, which is hereby incorporated by reference in its entirety. [0002] This invention was made with Government support under Contract No. R01 DK105015 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0003] The present disclosure relates to kinase inhibitor compounds and compositions and methods of their use. Background technique [0004] Dual-specificity tyrosine-regulated kinases (“DYRKs”) belong to the CMCG family of eukaryotic protein kinases and include CDK-like kinases (CLKs), glycogen synthase kinase 3 (GSK3), cyclin-dependent kinases (CDKs) and silk Mistogen-activated protein kinase (MAPK). DYRK family proteins self-activate through autophosphorylation of conserved tyrosine residues in the activation loop, which subsequently phosphorylates only serine and threonine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4745A61K31/5383A61K31/542
CPCA61K45/06C07D471/04A61P3/00A61P3/10A61P25/00A61P25/28A61K31/437
Inventor K·库玛P·王R·桑切斯A·G·奥卡尼亚A·斯图尔特R·戴维塔
Owner MT SINAI SCHOOL OF MEDICINE
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