Columbia University

University of Copenhagen

Kobenhavns Universitet

Kristian Stromgaard

Koji Nakanishi

Anders Bach

Makiko Suehiro

Stine B Vogensen

Stanislav Jaracz

Klaus Bertram Nissen

The present invention is directed to the provision of small molecule inhibitors of the PSD-95/NMDA receptor interaction, employing an undecapeptide corresponding to the C-terminal of the NMDA as a template for finding lead candidates. A compound (NMDAR/PSD-95 inhibitor) of the invention includes a peptide or peptide analog comprising at least four peptide bonded residues having the sequence YTXV or YSXV, wherein Y is selected from among E, Q, and A, or an analog thereof, and X is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analog thereof, wherein an amino-terminal residue of the peptide is N-alkylated. Alternatively the compound of the invention comprises a first peptide or peptide analog linked to a second peptide or peptide analog by a linker, where the first and second peptide or peptide analog each comprise at least four peptide bonded residues having the sequence YTXV or YSXV, wherein Y is selected from among E, Q, and A, or an analog thereof, and X is selected from among A, Q, D, N, N-Me-A, N-Me-Q, N-Me-D, and N-Me-N or an analog thereof.

Modified peptides as potent inhibitors of the PSD-95/NMDA receptor interaction

The present invention is directed to the provision of small molecule inhibitors of the PSD-95/NMDA receptor interaction, employing an undecapeptide corresponding to the C-terminal of the NMDA as a template for finding lead candidates. A compound (NMDAR/PSD-95 inhibitor) of the invention includes a peptide or peptide analogue comprising at least four peptide bonded residues having the sequence YTXV or YSXV, wherein Y is selected from among E, Q, and A, or an analogue thereof and 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, wherein an amino-terminal residue of the peptide is N-alkylated. Alternatively the compound of the invention comprises a first peptide or peptide analogue linked to a second peptide or peptide analogue by a linker, where the first and second peptide or peptide analogue each comprise at least four peptide bonded residues having the sequence YTXV or YSXV, wherein Y is selected from among E, Q, and A, or an analogue thereof, and 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.

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 (SEQ ID NO: 5) or YSXV (SEQ ID NO: 6), 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.

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

The subject invention provides compounds having the structure: wherein Ris H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; Ris H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; Ris H or OH; Ris H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; and wherein at least one of R, R, R, or Ris a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety, or an optically pure enantiomer of the compound or wherein R1 is H or OH; R2 is H, OH, halogen, unsubstituted or substituted, straight or branched (C-C) alkyl group, (C-C) alkenyl, or a (C-C) alkynyl, (C-C) alkoxy, (C-C) alkenyloxy, or (C-C) alkynyloxy, &#x2014;N3, &#x2014;COR5, &#x2014;CONR5R6, &#x2014;CO2R5, &#x2014;OCOR5, &#x2014;NH(OH), &#x2014;NR5R6, &#x2014;NHCOR5, &#x2014;N(OH)COR5, &#x2014;CH2OR5, &#x2014;OCH2CO2R5, &#x2014;CH2SR5, &#x2014;CH2NR5R6, &#x2014;SR5, &#x2014;OSR5, or &#x2014;NR5SO2R6, where R5 and R6 are each independently hydrogen, substituted or unsubstituted (C-C) alkyl, (C-C) alkenyl, or (C-C) alkynyl, or a cycloalkyl or aryl group having 3 to 10 carbon atoms; R3 is H or OH; R4 is H, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, -A-Ar, -A-Z-Ar, &#x2014;SO&#x2014;Ar, or -A-NR, or &#x2014;R, where A, Z and Ar are as defined herein, and the use of the compounds for detecting or identifying a receptor which binds the compounds of the invention or for treating a PAF associated condition in a subject.

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The subject invention provides ginkgolide C derivatives compounds having the structure: 

Synthesis of derivatives of ginkgolide C

The subject invention provides compounds having the structure: wherein Ris H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; Ris H, OH, a photoactivatable moiety, a fluorescent-moiety, or a radioactive moiety; Ris H or OH; Ris H, OH, a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety; and wherein at least one of R, R, R, or Ris a photoactivatable moiety, a fluorescent moiety, or a radioactive moiety, or an optically pure enantiomer of the compound or wherein R1 is H or OH; R2 is H, OH, halogen, unsubstituted or substituted, straight or branched (C&#x2013;C) alkyl group, (C&#x2013;C) alkenyl, or a (C&#x2013;C) alkynyl, (C&#x2013;C) alkoxy, (C&#x2013;C) alkenyloxy, or (C&#x2013;C) alkynyloxy, &#x2014;N3, &#x2014;COR5, &#x2014;CONR5R6, &#x2014;CO2R5, &#x2014;OCOR5, &#x2014;NH(OH), &#x2014;NR5R6, &#x2014;NHCOR5, &#x2014;N(OH)COR5, &#x2014;CH2OR5, &#x2014;OCH2CO2R5, &#x2014;CH2SR5, &#x2014;CH2NR5R6, &#x2014;SR5, &#x2014;OSR5, or &#x2014;NR5SO2R6, where R5 and R6 are each independently hydrogen, substituted or unsubstituted (C&#x2013;C) alkyl, (C&#x2013;C) alkenyl, or (C&#x2013;C) alkynyl, or a cycloalkyl or aryl group having 3 to 10 carbon atoms; R3 is H or OH; R4 is H, (C1&#x2013;C10) alkyl, (C1&#x2013;C10) alkenyl, (C1&#x2013;C10) alkynyl, -A-Ar, -A-Z-Ar, &#x2014;SO&#x2014;Ar, or -A-NR, or &#x2014;R, where A, Z and Ar are as defined herein, and the use of the compounds for detecting or identifying a receptor which binds the compounds of the invention or for treating a PAF associated condition in a subject.

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Roskilde, Denmark

Kristian Stromgaard