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High-affinity, dimeric inhibitors of psd-95 as efficient neuroprotectants against ischemic brain damage and for treatment of pain

A diacid and ethylene glycol technology, applied in the field of dimer peptide analogs, can solve the problem of side effects and cannot be used clinically

Active Publication Date: 2014-01-22
UNIVERSITY OF COPENHAGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NMDA receptor antagonists block sensitization of pain responses and exhibit good analgesic properties in animal models and clinical settings, but they suffer from unacceptable side effects and thus cannot be used clinically

Method used

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  • High-affinity, dimeric inhibitors of psd-95 as efficient neuroprotectants against ischemic brain damage and for treatment of pain
  • High-affinity, dimeric inhibitors of psd-95 as efficient neuroprotectants against ischemic brain damage and for treatment of pain
  • High-affinity, dimeric inhibitors of psd-95 as efficient neuroprotectants against ischemic brain damage and for treatment of pain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0111] According to a first embodiment, the dimeric PSD-95 inhibitor comprises a CPP linked directly or indirectly via a chemical bond to a nitrogen atom in the backbone of the NPEG linker in the inhibitor, wherein the nitrogen atom is symmetrically or asymmetrically located in the linker. The attachment of CPP to the nitrogen atom in the NPEG linker can be mediated via an amide bond, a maleimide coupling, a disulfide bond, or an amino-reactive electrophile selected from the group consisting of N-hydroxysuccinyl Amine (NHS) ester, p-nitrophenyl ester, succinimidyl carbonate, p-nitrophenyl carbonate, succinimidyl polyurethane, isocyanate, isothiocyanate, acyl azide, sulfuryl chloride, Aldehydes, carbonates, imidates or anhydrides, and thio-reactive groups selected from the group consisting of haloacetyls, haloalkane derivatives, aziridines, acryloyl derivatives arylating agents.

[0112] Alternatively, the attachment of the CPP to the nitrogen atom of the linker may be mediated...

Embodiment 1

[0165] Example 1. Synthesis of Dimeric PSD-95 Inhibitors

[0166] 1.1 Synthesis of Ns-NPEG4-diacid-linker A-C (Scheme 1- Figure 16 )

[0167] For the synthesis of Ns-NPEG4-diacid-linker A (3; Scheme 1), 2-chlorotrityl chloride resin (3 mmol, 1.90 g) was rinsed and swelled in DMF (20 min). Fmoc-NH-PEG was synthesized by adding 1 (2mmol, 800mg) in DMF (8mL) to the drained resin followed by DIPEA (10mmol, 1.75mL) 2 -CH 2 CH 2 COOH (1, Protocol 1; Biomatrik Inc., Jiaxing, China) was loaded onto the resin. After shaking for 60 minutes, methanol (1 mL, 25 mmol) was added and shaking was continued for another 5 minutes. Allow the loaded resin to drain, then rinse thoroughly with DMF (10-15 flowing washes, 10 ml each), deprotect the Fmoc group with 20% piperidine in DMF for 5 minutes, rinse with DMF in between, and then use DMF and THF rinse for 15 minutes. The resin was swelled in DIPEA (12 mmol, 2.1 mL) and THF (8 mL) for 15 min, then o-nitrobenzenesulfonyl chloride (NsCl,...

Embodiment 2

[0181] Example 2. Synthesis of labeled analogs of dimeric PSD-95 inhibitors

[0182] 2.1 Synthesis of fluorophore-labeled analogs (AB143, AB145, AB148, MS23)

[0183] AB145, AB145, AB148, and MS23 to prepare fluorescent ligands. Likewise, coupling of 5-FAM to Ns-deprotected resin-bound AB141 gave AB143. 5-FAM was coupled on a 0.07 mmol scale (NPEG-linker mole) in a total of 2 mL DMF containing N-site-resin / 5-FAM / HATU / collidine in a 1 / 2 / 2 / 3 ratio. For AB145, AB148, or MS23, the coupling time was 6 hours. For AB143, 5-FAM was coupled by continuous coupling for 6 hours and 16 hours, respectively.

[0184] 2.2 15 N, 13 Synthesis of C-labeled dimeric PSD-95 ligand

[0185] use the complete 15 N, 13 Fmoc-protected amino acid synthesis of C-labeled amino acid atoms[ 15 N, 13 C]-PEG4 (IETAV) 2 (AB140) (Cambridge Isotope Laboratories, Inc., Andover, MA, USA). The amino acid building block side chains of Thr and Glu are protected with tert-butyl groups. Labeled Fmoc-Val-OH...

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Abstract

The invention provides novel potent inhibitors of the ternary protein complex of nNOS, PSD-95, and the NMDA receptor and pharmaceutical compositions comprising the inhibitors for prophylaxis and / or treatment of excitotoxic-related disease and chronic pain conditions in a subject. The inhibitors are dimeric PSD-95 inhibitors comprising a first peptide or peptide analogue linked to a second peptide or peptide analogue by a linker, wherein the first and the second peptide or peptide analogue comprise at least four amide-bonded residues having a sequence YTXV or YSXV, wherein a. Y is selected from among E, Q, and A, or an analogue thereof, and b. X is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analogue thereof, and wherein a Cell Penetrating Peptide (CPP) is linked to the linker or to an amino acid side chain of the first and second peptide or peptide analogue. The linker can be a PEG or NPEG linker.

Description

technical field [0001] The scaffold protein PSD-95 is a potential target for the treatment of ischemic stroke and traumatic brain injury, as well as for chronic pain conditions (eg, neuropathic and inflammatory pain). The present invention relates to the supply of dimeric peptide analogs useful as inhibitors of PSD-95-related protein-protein interactions. Background technique [0002] Protein-protein interactions (PPIs) are critical for important cellular processes and are implicated in a variety of pathophysiological states, where they serve as potential targets for therapeutic intervention. PPIs have generally been considered difficult targets for therapeutic molecules because they are often characterized by large, flat, and hydrophobic interfaces. [0003] One class of PPIs is the one involving the PDZ domain [PDZ is the postsynaptic density protein-95 (PSD-95), the Drosophila homologous discoid giant tumor suppressor (DlgA) and the zonule atres-1 protein (ZO-1 )abbrevi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61P25/00
CPCA61K38/17A61P25/00A61P25/04A61P9/10A61K47/50
Inventor A·巴赫K·斯特罗姆戈德
Owner UNIVERSITY OF COPENHAGEN
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