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Optimization of Monocarboxylate Transporter 1 Blockers through Analysis and Modulation of Atropisomer Interconversion Properties

2006; American Chemical Society; Volume: 50; Issue: 2 Linguagem: Inglês

10.1021/jm060995h

1520-4804

Simon D. Guile, John R. Bantick, Martin Cooper, David K. Donald, C. Eyssade, Anthony H. Ingall, Richard J. Lewis, Barrie Martin, Rukhsana T. Mohammed, Timothy J. Potter, Rachel Reynolds, Stephen A. St-Gallay, Andrew D. Wright,

Cancer therapeutics and mechanisms

We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.