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. 2013 Oct 10;56(19):7636-50.
doi: 10.1021/jm401037h. Epub 2013 Oct 1.

Substrate-based fragment identification for the development of selective, nonpeptidic inhibitors of striatal-enriched protein tyrosine phosphatase

Tyler D Baguley  1 , Hai-Chao Xu, Manavi Chatterjee, Angus C Nairn, Paul J Lombroso, Jonathan A Ellman
Affiliations

Substrate-based fragment identification for the development of selective, nonpeptidic inhibitors of striatal-enriched protein tyrosine phosphatase

Tyler D Baguley et al. J Med Chem. .

Abstract

High levels of striatal-enriched protein tyrosine phosphatase (STEP) activity are observed in a number of neuropsychiatric disorders such as Alzheimer's disease. Overexpression of STEP results in the dephosphorylation and inactivation of many key neuronal signaling molecules, including ionotropic glutamate receptors. Moreover, genetically reducing STEP levels in AD mouse models significantly reversed cognitive deficits and decreased glutamate receptor internalization. These results support STEP as a potential target for drug discovery for the treatment of Alzheimer's disease. Herein, a substrate-based approach for the discovery and optimization of fragments called substrate activity screening (SAS) has been applied to the development of low molecular weight (<450 Da) and nonpeptidic, single-digit micromolar mechanism-based STEP inhibitors with greater than 20-fold selectivity across multiple tyrosine and dual specificity phosphatases. Significant levels of STEP inhibition in rat cortical neurons are also observed.

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Figures

Figure 1
Figure 1
Selected initial substrate hits obtained against STEP.
Figure 2
Figure 2
DFMP inhibitors 11 and 12 based on privileged substrate scaffolds 6 and 8.
Figure 3
Figure 3
Additional analogs based upon inhibitor 12m.
Figure 4
Figure 4
Rat cortical neurons were treated with vehicle or 12s (a) or 12t (b) (concentrations of 0.1, 1 or 10 µM) for 1 h and analyzed by Western blotting. (*p<0.05; **p<0.01; ***p<0.001 one-way ANOVA, Dunnett’s post hoc). Data represent the phospho-signal normalized to the total protein signal and GAPDH ± s.e.m. (n = 3–5 each group).
Scheme 1
Scheme 1
Inhibitor Synthesis through Suzuki-Miyaura Cross-Coupling. aReagents: (a) ArBLn, PdCl2, CyJohnPhos, K2CO3, dioxane/H2O; (b) ArBLn, Pd(PPh3)4, Na2CO3, DME/EtOH/H2O.
Scheme 2
Scheme 2
Synthesis of Arylboronic Acids 17a aReagents: (a) N-bromosuccinimide, N,N-diisopropylamine, CH2Cl2; (b) n-butyllithium, Et2O; B(OMe)3; aqueous HCl.
Scheme 3
Scheme 3
Synthesis of Aryltrifluoroborates 18a aReagents: (a) n-butyllithium, Et2O; (b) ketone; aqueous NH4Cl; (c) Et3SiH, F3CCOOH, CH2Cl2; (d) Et2SiH2, [Ir(cod)Cl]2, benzene; B2pin2, HBpin, [Ir(cod)Cl]2, dtbpy, THF; aqueous KHF2.
Scheme 4
Scheme 4
Synthesis of Diarylmethane-based Boron Reagents 22 and 24a aReagents: (a) PhMgBr, Et2O or 1-bromo-3-iodobenzene, n-butyllithium, THF; aldehyde; (b) Et3SiH, F3CCOOH, CH2Cl2; (c) Pd(dppf)Cl2, KOAc, B2pin2, DMSO; (d) n-butyllithium, THF; 3,4-dichlorobenzaldehyde.
Scheme 5
Scheme 5
Synthesis of α-Hydroxymethylphosphonic Acid Inhibitors 11o and 12ra aReagents: (a) Pd(PPh3)4, Na2CO3, DME/EtOH/H2O; (b) NaBH4, MeOH.
Scheme 6
Scheme 6
Synthesis of the Four Stereoisomeric α-Hydroxymethylphosphonic Acid Inhibitors 12s to 12va aReagents (a) P(OMnt)3, TMSCl, 0 °C; separation of diastereomers by recrystallization; (b) TMSCl, NaI, CH3CN; (c) i. n-butyllithium, tBuOMe; ii. ZnCl2; iii. n-butyllithium; iv. tetraethylethylenediamine, toluene; v. (+)-MIB or (−)-MIB (10% mol); vi. 3-bromobenzaldehyde; (d) Pd(dppf)Cl2, KOAc, B2Pin2, DMSO; (e) Pd(PPh3)4, Na2CO3, DME/EtOH/H2O.
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