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Conjugates useful in treatment of prostate cancer

A technology for prostate cancer and conjugates, which can be used in medical preparations and pharmaceutical formulations of non-active ingredients, and can solve problems such as unclear significance

Inactive Publication Date: 2000-01-26
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PSA also forms a stable complex with α2-macroglobulin, but the significance of this complex formation in vivo as a consequence of PSA encapsulation and complete absence of PSA epitopes is unclear

Method used

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  • Conjugates useful in treatment of prostate cancer
  • Conjugates useful in treatment of prostate cancer
  • Conjugates useful in treatment of prostate cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0233] Another embodiment of the oligopeptide-cytotoxic agent conjugate of the present invention or a pharmaceutically acceptable salt thereof, which is preferably vinblastine and deacetylvinblastine, described by the following general formula III: in:

[0234] The oligopeptide is an oligopeptide that is selectively recognized by free prostate-specific antigen (PSA) and can be proteolytically cleaved by the enzymatic activity of free prostate-specific antigen, and the oligopeptide includes cyclic amino acids of the following general formula:

[0235] R g and R h independently selected from hydrogen atom, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-OH,-C 1 -C 6 Alkyl-di-OH, -C 1 -C 6 Alkyl-tri-OH and

[0236] Condition is R d and R e At least one of them is not a hydrogen atom or C 1 -C 6 alkyl, or

[0237] R g and R h Joint Formation - CH 2 CH 2 OCH 2 CH 2 - double radicals;

[0238] R 19 is a hydrogen atom, (C 1 -C 3 Alkyl)-CO or chlorine substituted (C 1 -C...

Embodiment 1

[0274] Preparation of oligopeptides containing a PSA-mediated cleavage site

[0275] In the Applied Biosystems 430A automatic peptide synthesizer, amino acids were introduced by double coupling method, and protected oligopeptides were prepared by solid-phase synthesis. Treatment with liquid hydrofluoric acid achieves the purpose of deprotecting and removing the oligopeptide from the resin support. The oligopeptide was purified by preparative high pressure liquid chromatography on a reverse phase C18 silica gel column eluting with a 0.1% aqueous trifluoroacetic acid / acetonitrile gradient. Oligopeptide identity and homogeneity were confirmed by amino acid composition analysis, high pressure liquid chromatography, and fast atom bombardment mass spectrometry. The oligopeptides prepared by this method are shown in Table 2.

[0276] SEQ.ID.NO.

Peptide / Peptide-DOX Conjugate

Cleavage by PSA

50% substrate required

the time you want

(Min...

Embodiment 2

[0280] Evaluation of oligopeptides recognized by free PSA

[0281] The oligopeptides prepared in Example 1 were individually dissolved in PSA digestion buffer (12mM tris(hydroxymethyl)aminomethane pH8.0, 25mM sodium chloride, 0.5mM calcium chloride) and the solution was mixed in a molar ratio of 100 to 1 added to the PSA. Alternatively, the PSA digestion buffer used was 50 mM tris(hydroxymethyl)-aminomethane pH 7.4, 140 mM sodium chloride. The reaction was stopped after various reaction times by adding trifluoroacetic acid (TFA) to a final concentration of 1% (vol / vol). Alternatively stop the reaction with 10 mM zinc chloride. The quenched reaction was analyzed by HPLC on a reverse phase C18 column eluting with a 0.1% TFA / acetonitrile gradient. The evaluation results are shown in Table 2. Table 2 shows the time (minutes) required for 50% cleavage of the oligopeptides with enzymatically active free PSA. Oligopeptides containing free amine moieties (ie containing hArg, Orn,...

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Abstract

Chemical conjugates which comprise oligopeptides, having amino acid sequences that are selectively proteolytically cleaved by free prostate specific antigen (PSA) and known cytotoxic agents are disclosed. Such conjugates are useful in the treatment of prostatic cancer and benign prostatic hypertrophy.

Description

Background of the invention [0001] In 1994, an estimated 200,000 men in the United States were diagnosed with prostate cancer and 38,000 American men would die from the disease (Garnick, M.B. (1994). The Dilemmas of Prostate Cancer . Scientific American), April: 72-81). Thus, prostate cancer is the most prevalent malignancy (besides skin cancer) and the second leading cause of cancer-related mortality (after lung cancer) among American men. [0002] Prostate-specific antigen (PSA) is a single-chain 33 kDa glycoprotein that is almost exclusively produced by the human prostate epithelium at concentrations ranging from 0.5 to 2.0 mg / ml in human semen (Nadji, M., Taber, S.Z., Castro, A. etc., (1981) Cancer 48:1229; Papsidero, L., Kuriyama, M., Wang, M. et al., (1981). JNCI 66:37; Qui, S.D., Young, C.Y.F., Bihartz , D.L., etc., (1990), "Journal of Urology" (J.Urol.) 144: 1550; Wang, M.C., Valenzuela, L.A., Murphy, G.P., etc., (1979). "Urology Research" (Invest.Urol. )17:159). T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64C07C
Inventor V·M·加斯凯冯冬梅D·德菲奥-琼斯
Owner MERCK & CO INC
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