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Iap binding compounds

a technology of iap and binding compounds, which is applied in the direction of instruments, peptides/protein ingredients, peptides, etc., can solve the problems of short half-life due to proteolytic degradation in the body, lack of molecular specificity of therapies, and inability to disclose or teach structural bases, etc., to achieve easy or less expensive synthesizing, the effect of improving the pharmacologic properties

Inactive Publication Date: 2010-10-14
THE TRUSTEES OF PRINCETON UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these therapies lack molecular specificity, and more specific molecular targets are needed.
However, the patent neither discloses nor teaches a structural basis for choosing a particular peptide fragment of Smac for use as a therapeutic agent or target.
These include short half-life due to proteolytic degradation in the body, low absorption through intestinal walls and potential immunogenic reactions, as well as expense involved in peptide synthesis.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Certain Compounds of the Invention and Components Thereof

[0142]

[0143](4-bromo-butyl)-benzene (50 a) (PAA 2-68). Phosphorus tribromide (1.10 mL, 11.2 mmol) was added dropwise to (4-hydroxy-butyl)-benzene (5.04 g, 33.5 mmol) and stirred 1 h under argon at 23° C. The flask was then heated to 100° C. via silicone oil bath and allowed to stir 4 h. The reaction mixture was cooled, quenched with several mL of cold H2O, diluted with ether, washed with brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to 6.32 g (88%) of colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.18-7.33 (m, 5H), 3.44 (t, J=6.9 Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 1.76-1.96 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ 147.8, 128.4, 125.8, 35.0, 33.7, 32.2, 29.8.

[0144](5-bromo-pentyl)-benzene (50 b) (PAA 67). Phosphorus tribromide (0.47 mL, 5.0 mmol) was added dropwise to (5-hydroxy-pentyl)-benzene (1.98 g, 12.0 mmol) and stirred 1 h under argon at 23° C. The flask was then heated to 100° C. via silicone oil...

example 2

Synthesis of Certain Oxazole Compounds

[0173]Synthetic scheme for oxazole compounds

[0174]I. Formation of Boc-Ala-Ser-OMe (3):

[0175]1 eq. of Boc-Ala-succinimide ester (2) was added to an ice-cold solution of DIPEA (2 eq.) and H-Ser-methyl ester hydrochloride (R=H) or H-Thr-methyl ester hydrochloride (R=CH3) (1) in dry THF under argon. The solution was allowed to warm to RT and stirred overnight (Rocchi, R. et al. (1987) Int. J. Peptide Protein Res. 30, 240-256). The THF was removed in vacuo, the resin was brought up in ethyl acetate and washed three times each with saturated sodium bicarbonate, 5% citric acid and saturated sodium chloride. The solution was dried with magnesium sulfate and the solvent was removed in vacuo leaving a white solid. Single spot on TLC (1:10 MeOH / CHCl3). No purification was necessary. 75% yield.

[0176]II. Formation of Boc-Ala-Ser-OMe Oxazoline (4):

[0177]1.05 eq. Burgess' reagent was added in one portion to a stirred solution of 3 in dry THF and the resulting ...

example 3

Synthesis of Compounds Containing Proline or Phenylalanine Derivatives

[0186]Materials. Unless otherwise stated, materials were purchased from Aldrich Chemical Co. (Milwaukee, Wis.) or Fisher Scientific (Pittsburgh, Pa.) and used without further purification. All unnatural phenylalanine derivatives were purchased from Advanced ChemTech (Louisville, Ky.) or Novabiochem (Calbiochem, San Diego, Calif.) as the Fmoc protected amino acid. These and the proline derivatives were used in peptide synthesis in the same manner as a naturally-occurring amino acid would be. Methylbenzhydrylamine (MBHA) solid-phase peptide synthesis resin, Rink amide resin, and 9-Fluorenylmethoxycarbonyl (Fmoc) protected amino acids were obtained from Advanced ChemTech (Louisville, Ky.) and NovaBiochem (San Diego, Calif.). 6-Bromoacetyl-2-dimethylaminonaphthalene (badan) dye was obtained from Molecular Probes (Eugene, Oreg.).

[0187]Peptide synthesis. Peptide molecules were synthesized on an Advanced ChemTech 396 MPS...

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PUM

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Abstract

Compounds that bind cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The compounds are mimetics of the N-terminal tetrapeptide of IAP-binding proteins, such as Smac / DIABOLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these compounds for therapeutic, diagnostic and assay purposes.

Description

[0001]This application is a continuation of U.S. application Ser. No. 10 / 521,723, filed Apr. 10, 2006, which is a 371 of International Application No. PCT / US03 / 22071, filed Jul. 15, 2003, which claims the benefit of U.S. Provisional Application No. 60 / 395,918, filed Jul. 15, 2002, the entirety of which is incorporated by referenced therein.[0002]This application is a continuation of U.S. application Ser. No. 10 / 521,723, filed July Apr. 10, 2006, which is a continuation-in-part of International Application No. PCT / US02 / 17342, filed May 31, 2002, which claims the benefit of U.S. Provisional Application No. 60 / 294,682 filed May 31, 2001 and U.S. Provisional Patent Application No. 60 / 345,630 filed Jan. 3, 2002. U.S. application Ser. No. 10 / 521,723, filed Jul. 15, 2003, is also a continuation-in-part of U.S. application Ser. No. 09 / 965,967, filed Sep. 28, 2001, now U.S. Pat. No. 6,992,063 issued Jan. 31, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60 / 236,574...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D207/06C07K5/06C07K5/097C07K5/103
CPCA61K38/00C07K5/06026G01N33/574C07K5/1008C07K5/0821
Inventor SHI, YIGONGSEMMELHACK, MARTIN F.CASE, MARTINALBINIAK, PHILIP A.MCLENDON, GEORGEKIPP, RACHAEL A.WIST, AISLYN D.
Owner THE TRUSTEES OF PRINCETON UNIV
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