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. 2010 Aug 15;18(16):5995-6005.
doi: 10.1016/j.bmc.2010.06.071. Epub 2010 Jun 25.

Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R)

William Engen  1 , Terrence E O'Brien, Brendan Kelly, Jacinda Do, Liezel Rillera, Lance K Stapleton, Jack F Youngren, Marc O Anderson
Affiliations

Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R)

William Engen et al. Bioorg Med Chem. .

Abstract

The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3-5 microM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding.

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Figures

Figure 1
Figure 1
Design of novel aryl-heteroaryl ureas (AHUs) based on lead scaffold 1. This publication focuses on the approach outlined in equation 3.
Figure 2
Figure 2
Overview of aryl-heteroaryl urea library derived from heteroaryl amine chemset 3 and substituted aryl chemset 4. The composition of the library is outlined in Table 1.
Figure 3
Figure 3
Synthesis of aryl-heteroaryl ureas 2{a,b} and undesired formation of symmetrical ureas 5{b}.
Figure 4
Figure 4
Computational docking of the relatively potent AHU inhibitor 2{2,1} into the active site of IGF-1R kinase. (a): 3-dimensional side-view of postulated inhibitor-protein complex; (b): two dimensional diagram showing key interactions with the ATP-binding site of IGF-1R. This inhibitor orientation will be referred to as “Binding Mode A”.
Figure 5
Figure 5
Summary of most potent compounds identified in this study, with in vitro kinase potency indicated (μM), with error in parenthesis.
Scheme 1
Scheme 1
Synthesis of aryl-heteroaryl ureas derived from 4-amino-2-trifluoromethylquinoline. Reagents and conditions: (a) NaN3, 15-crown-5, 1-butanol; (b) H2, Pd/C, CH3OH; (c) Ar-NCO, NaOtBu, DMSO.
Scheme 2
Scheme 2
Synthesis of aryl-heteroaryl ureas derived from 4-amino-1,8-napthyridine and 4-amino-1,8-tetrahydronapthyridine. Reagents and conditions: (a) methyl acetoacetate, POCl3; (b) acetone, POCl3; (c) NaN3, 15-crown-5, CH3OH; (d) H2, cat. PtO2 or Pd/C; (e) NaBH4, CH3OH; (f) Ar-NCO, DMSO.
Scheme 3
Scheme 3
Synthesis of aryl-heteroaryl ureas derived from 4-amino-1,7-napthyridine. Reagents and conditions: (a) acetone, POCl3; (b) NaN3, 15-crown-5, CH3OH; (c) H2, cat. PtO2; (d) aryl isocyanate, DMSO; (e) ethyl acetoacetate, POCl3.
Scheme 4
Scheme 4
Synthesis of aryl-heteroaryl ureas derived from 4-amino-2-chloroquinoline and 4-amino-2-oxoquinoline. Reagents and conditions: (a) POCl3; (b) aq. HCl, 1,4-dioxane; (c) NaN3, 15-crown-5, CH3OH; (d) H2, Pd/C, CH3OH; (e) NaBH4, CH3OH; (f) Ar-NCO, DMSO.
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