Macrocyclic kinase inhibitors macrocycle design

Based on the crystallographic analysis of a complex of checkpoint kinase 1 (Chkl) with an acyclic pyrazinyl urea-based inhibitor, and molecular modeling, a class of macrocyclic Chkl inhibitors vras designed by Abbott (Figure 5.4). These novel Chkl inhibitors exhibited excellent selectivity over a panel of more than 70 kinases. The 14- and 15-membered macrocycles, 20 and 21, were equipotent while the 16-membered analog was approximately 4-fold less active (IC50 = 28 nM) presumably due to reduced... 

Designed Macrocyclic Kinase Inhibitors Table 5.7 SAR of substituents in the A-ring."... 

The design of a novel series of cycUn-dependent kinase (CDK) inhibitors with a macrocyclic quinoxaline-2-one 208 is reported (Kawanishi et al. 2006), where 208 was synthesized as shown in Scheme 5.50. The deprotonation of the fluorine-adjacent position of l-fluoro-2-iodobenzene 209, with LDA, followed by the carbon dioxide trapping and then esterification of the carboxylic acid, led to methyl 2-fluoro-3-iodobenzoate. The iodomagnesium exchange of methyl 2-fluoro-3-iodobenzoate according to Knochel s procedure (Knochel et al. 2003) followed by chloroglyoxylic acid ethyl ester resulted in ketoester 210, which was coupled with 3-[(tert-bulyldimethylsilyl)oxy]benzene-1,2-diamine to... 

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