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CN-121974889-A - FAP-targeted multimeric compound and preparation method and application thereof

CN121974889ACN 121974889 ACN121974889 ACN 121974889ACN-121974889-A

Abstract

The application relates to the technical field of biological medicines, and discloses a FAP-targeted polymer compound, a preparation method and application thereof. The FAP-targeting multimeric compound has a chemical structure shown in any one of formulas (1) - (3), and comprises 3-6 targeting moieties of fibroblast activation protein alpha (FAP-alpha). Compared with the existing compound, the FAP-targeted multimeric compound has higher tumor uptake and longer tumor residence time, and can clearly display the position and range of tumors and timely discover the remote metastasis of the tumors in the diagnosis and treatment of FAP positive tumors, thereby providing more comprehensive disease assessment.

Inventors

  • Request for anonymity

Assignees

  • 北京济核生物科技有限责任公司

Dates

Publication Date
20260505
Application Date
20251112

Claims (9)

  1. 1. The FAP-targeted multimeric compound is characterized by having a chemical structure shown in any one of formulas (1) - (3): (1) (2) (3) Wherein n and m are selected from any integer of 0 to 12; The structural unit B is a targeting part of fibroblast activation protein alpha (FAP-alpha); the structural units D and Y are connecting groups, one of which is absent or absent at the same time, and are selected from any one of the following structures: ; Wherein n 1 、n 2 、n 3 is any integer from 1 to 12, X 1 、Y 1 is selected from C, N, O, S, and R 1 、R 2 is independently selected from hydrogen or any one of the following structures: ; Wherein X is halogen; the structural unit E is selected from any one of the following structures: ; the structural unit E2 is selected from any one of the following structures: ; The structural unit E3 is selected from any one of the following structures: ; the structural unit Z is selected from at least one of a radioactive moiety, a chelating agent, a fluorescent dye, a contrast agent or a cytotoxic substance.
  2. 2. The compound of claim 1, wherein B has the structural formula: ; Wherein each R a 、R b is independently selected from hydrogen, hydroxy, C 1-6 hydrocarbyl, mercapto, or halogen; R c is selected from H, -CN, -B (OH) 2 , chloroacetyl, -C (O) hydrocarbyl, -C (O) aryl, -c=c-S (O) 2 aryl, -CO 2 H、-NH 2 , ureido, -SO 3 H、-PO 3 H 2 , ketoamide, trifluoromethyl, trifluoroacetyl and tetrazolyl; R d is selected from H, C 1-8 straight or branched hydrocarbon or hydroxy; R e is selected from 5-to 10-membered aromatic mono-or bi-cyclic, 5-to 10-membered non-aromatic mono-or bi-cyclic, 5-to 10-membered aromatic mono-or bi-cyclic heterocycle, 5-to 10-membered non-aromatic mono-or bi-cyclic heterocycle and R e does not include a pyridine ring; Wherein the heterocyclic ring contains 1-3 hetero atoms selected from O, N or S, and the hydrogen of R e can be substituted by halogen, -NHC 1-8 alkyl, -OH, when R e is When it does not include an amine substituent; r f has the structural general formula Wherein R f1 、R f2 、R f3 、R f4 is each present or absent; r f1 is O, S, NR g ,R g is hydrogen, halogen, hydroxy, mercapto or C 1-8 alkyl; R f2 is C 1-8 alkyl or N 4 = any integer from 0 to 8; R f3 is an aromatic or non-aromatic monocyclic nitrogen-containing heterocycle, and is selected from any one of the following structural species: ; R f4 is absent or selected from any one of the following structures: ; wherein n 1 、n 2 、n 3 is any integer from 1 to 12.
  3. 3. The FAP-targeted multimeric compound of claim 2, wherein R e is selected from any one of the following structures, any of which ring and any of the ring substituents may be extended to join R f : 。
  4. 4. The FAP-targeted multimeric compound of claim 2, wherein structural unit B comprises any one of the following chemical structures: ; ; 。
  5. 5. the FAP-targeted multimeric compound of claim 1, wherein: The chelating agent comprises DOTA、DOTAGA、NOTA、NOTAGA、TETA、DAPA、TRAP、HBED-CC、DFO、PCTA、DTPA、HYNIC、ATSM、EDTA、CB-TE2A、NOPO、NOTAM、MAG3、Deferoxamine、Cyclen、H3RESCA、Octaaminocryptands、 diaza 18-crown-6, NTA, CB-cyclam or isocyanide; The radioactive moiety is selected from isotopes that emit alpha rays, beta rays, gamma rays, auger electrons, X rays, or fluorescence; The fluorescent dye comprises at least one of xanthine, acridine, oxazine, cyanine, styryl dye, coumarin, porphyrin, metal ligand-complex, fluorescent protein, nanocrystal, perylene, boron dipyrromethene or phthalocyanine; The cytotoxic substance comprises at least one of MMAE, MMAF, DM, PNU-159582, cryptophycin-55, PBD or Epothilone B.
  6. 6. A pharmaceutical composition comprising the FAP-targeted multimeric compound of any one of claims 1-5.
  7. 7. A FAP inhibitor comprising the FAP-targeting multimeric compound of any one of claims 1-5, a salt or isomer of the FAP-targeting multimeric compound.
  8. 8. Use of the pharmaceutical composition of claim 6 or the FAP inhibitor of claim 7 for the manufacture of a medicament for the treatment or detection of a disease characterized by overexpression of fibroblast activation protein FAP.
  9. 9. The use according to claim 8, wherein the disease characterized by overexpression of fibroblast activation protein FAP comprises any of cancer, chronic inflammation, atherosclerosis, fibrosis, tissue remodeling or scar disease.

Description

FAP-targeted multimeric compound and preparation method and application thereof Technical Field The application relates to the technical field of biological medicine, in particular to a FAP-targeted polymer compound and a preparation method and application thereof. Background Tumor-associated fibroblasts are an extremely important component of the tumor microenvironment, and fibroblast activation protein FAP is recognized as a tumor-associated fibroblast marker, which can promote tumor development and invasion. FAP belongs to the type II transmembrane serine protein of the proline oligopeptidase family, which is more unique in that it has both endopeptidase and exopeptidase activities and is highly expressed in the epithelial tumor stroma (and other diseases involving tissue remodeling), while being underexpressed or even unexpressed in normal tissues, is a good target for tumor imaging and therapy. FAP inhibitors (FAPI) exhibit extremely high affinity and specificity for FAP and find application in the diagnosis of a variety of solid tumors. The prior FAPI small molecular compound takes (4-quinolinyl) -glycyl-2-cyano pyrrolidine as a core structure and has made important progress in the field of targeted tumor imaging, the German Heidelberg research group takes the (4-quinolinyl) -glycyl-2-cyano pyrrolidine as a core structure to develop first-time targeted FAP drugs of FAPI-03 to FAPI-15, wherein 68Ga-FAPI-04 has the best effect and good tumor visualization capability, kratochwil and the like apply 68Ga-FAPI-04 to 80 patients suffering from 28 different types of solid tumors, and the drug is found to perform well in most focuses 68 Ga-FAPI-04. The later-developed 68Ga-FAPI-46 further improves the uptake and residence time of the drug in tumor emergence, has better tumor background ratio compared with 68Ga-FAPI-04, and has great development potential in the application of 68Ga-FAPI in tumor diagnosis. FAPI the use of FAPI in tumors and other diseases characterized by overexpression of fibroblast activation protein is closely related to their structure, and structural analysis and design of FAPI is an important way to produce FAPI with excellent metabolic properties and to apply FAPI for disease diagnosis and treatment. Based on this, it is important to design a novel FAP inhibitor with excellent pharmacokinetic properties. Disclosure of Invention The application provides a FAP-targeted multimeric compound, a preparation method and application thereof, and aims to develop a novel FAP inhibitor with excellent pharmacokinetic properties and use the FAP inhibitor as a medicament for diagnosing and treating various diseases caused by over-expression of Fibroblast Activation Protein (FAP). In order to achieve the above purpose, the present application is realized by the following technical scheme. In a first aspect of the present application, there is provided a FAP-targeted multimeric compound having a chemical structure according to any one of formulae (1) to (3): (1) (2) (3) Wherein n and m are selected from any integer of 0 to 12; The structural unit B is a targeting part of fibroblast activation protein alpha (FAP-alpha); the structural units D and Y are connecting groups, one of which is absent or absent at the same time, and are selected from any one of the following structures: Wherein n 1、n2、n3 is any integer from 1 to 12, X 1、Y1 is selected from C, N, O, S, and R 1、R2 is independently selected from hydrogen or any one of the following structures: Wherein X is halogen; the structural unit E is selected from any one of the following structures: the structural unit E2 is selected from any one of the following structures: The structural unit E3 is selected from any one of the following structures: the structural unit Z is selected from at least one of a radioactive moiety, a chelating agent, a fluorescent dye, a contrast agent or a cytotoxic substance. Preferably, the structural formula of the structural unit B is as follows: Wherein each R a、Rb is independently selected from hydrogen, hydroxy, C 1-6 hydrocarbyl, mercapto, or halogen; R c is selected from H, -CN, -B (OH) 2, chloroacetyl, -C (O) hydrocarbyl, -C (O) aryl, -c=c-S (O) 2 aryl, -CO 2H、-NH2, ureido, -SO 3H、-PO3H2, ketoamide, trifluoromethyl, trifluoroacetyl and tetrazolyl; R d is selected from H, C 1-8 straight or branched hydrocarbon or hydroxy; R e is selected from 5-to 10-membered aromatic mono-or bi-cyclic, 5-to 10-membered non-aromatic mono-or bi-cyclic, 5-to 10-membered aromatic mono-or bi-cyclic heterocycle, 5-to 10-membered non-aromatic mono-or bi-cyclic heterocycle and R e does not include a pyridine ring; Wherein the heterocyclic ring contains 1-3 hetero atoms selected from O, N or S, and the hydrogen of R e can be substituted by halogen, -NHC 1-8 alkyl, -OH, when R e is When it does not include an amine substituent; r f has the structural general formula Wherein R f1、Rf2、Rf3、Rf4 is each present or absent; r f1 is O, S, NR g,Rg is hydro