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cell membrane via passive diffusion is dramatically
reduced. Our O-malonic acid system is chemically set up
to investigate this possibility. When one of the acid
groups is converted to an amide group, monoacid 16
displayed reduced potency against PTP1Bwith a Ki of
13.8 mM (Table 2). When a cyclopropyl is added to the
primary amide, monoacid 17 maintained most of the
potency of the corresponding diacid and has a Ki of 8.4
mM, and selectivity over TCPTP greater than 23.8-fold,
which represent the most potent and most selective
monoacid reported so far.
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In summary, we have linked second-site binding salicyl-
ate to three different classes of phosphotyrosine mimet-
ics and the resulting molecules are novel, potent and
selective PTP1Binhibitors. Analogues derived from
monoacid 17 are currently under investigation and
inhibitors which display cellular activities will be repor-
ted shortly.
References and Notes
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5. For instance, TCPTP knock-out mice died at 3–5 weeks
after birth. See: You-Ten, K. E.; Muise, E. S.; Itie, A.;
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19. The coordinates have been deposited to Protein Data
Bank under the file name of 1PYN.
20. Szczepankewicz, B. G.; Liu, G.; Hajduk, P. J.; Abad-
Zapatero, C.; Pei, Z.; Xin, Z.; Lubben, T.; Trevillyan, J. M.;
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