6582
D. R. Adams et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6579–6583
Scheme 2. Reagents and conditions: (a) n-BuLi THF, À78 °C then F3CC(O)CO2Et (50%); (b) 10% CF3CO2H/CH2Cl2 (quant.); (c) 13 (Ref. 16),
diisopropyl azodicarboxylate, PBu3, THF, rt (25%); (d) KOH, EtOH aq, 60 °C (34%-quant.); (e) Ac2O, Et3N, CH2Cl2 (quant.); (f) H2, Pd-C, EtOAc,
rt (quant.); (g) 13 (Ref. 16), diisopropyl azodicarboxylate, PPh3, THF, rt (79%); (h) KOH, EtOH, PhMe, 0 °C (quant.); (i) F3CC(O)CO2Et, Et3N,
PhMe, rt (30%); (j) RBr, K2CO3, DMF, rt [yields for nn-ester precursors: 19 (64%), 20 (75%), 21 (quant.), 22 (84%), 23 (40%), 24 (88%), 25 (89%)].
References and notes
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Figure 2. Docked model of (S)-19 (black stick/mesh surface) in the
B.; Peters, G. H.; Norris, K.; Olsen, O. H.; Jeppesen, C.
PTP1B catalytic site; PTP1B solvent accessible surface is shown (solid;
B.; Lundt, B. F.; Ripka, W.; Møller, K. B.; Møller, N. P.
color coding as Fig. 1).
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assay with para-nitrophenyl phosphate at pH 7.0.14
(b) Lee, S.; Wang, Q. Med. Res. Rev. 2007, 27, 553;
Computational docking15 of compound 19 (Fig. 2) sup-
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ported the proposed binding model in which the chlor-
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13, 199; (f) Taylor, S. D. Curr. Top. Med. Chem. 2003, 3,
the benzyloxy group folds over Tyr46. Interestingly,
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(25) was substantially detrimental to activity. This is
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consistent with the requirement for a hydrophobic
7. Salmeen, A.; Andersen, J. N.; Myers, M. D.; Tonks, N.
extension from the core structure envisaged in our bind-
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In summary, conformational mobility, a small enclosed
catalytic pocket, and extensive substrate contacts out-
with the active site present challenges for the design of
PTP1B inhibitors. Here, we have used a structure-based
approach to design novel 2-aryl-3,3,3-trifluoro-2-
hydroxypropionic acid ligands for the PTP1B 1° site.
These compounds exhibit PTP1B inhibitory activity in
a cell-based assay and provide a starting point for a
new series of non-peptidic, mono-acid PTP1B inhibitors.
10. (a) Liu, G.; Xin, Z. L.; Pei, Z. G.; Hajduk, P. J.; Abad-
Zapatero, C.; Hutchins, C. W.; Zhao, H. Y.; Lubben, T.
H.; Ballaron, S. J.; Haasch, D. L.; Kaszubska, W.;
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Xin, Z. L.; Serby, M. D.; Pei, Z. H.; Szczepankiewicz, B.
G.; Hajduk, P. J.; Abad-Zapatero, C.; Hutchins, C. W.;
Lubben, T. H.; Ballaron, S. J.; Haasch, D. L.; Kaszubska,