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Design method of covalent drugs

A design method and drug technology, applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve problems such as high risk of side effects, obvious drug tolerance, and inability to design covalent drugs, achieve strong biological activity, improve The effect of binding capacity, increasing medication adherence

Active Publication Date: 2019-12-10
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

The covalent drug molecule is mainly covalently coupled with the group on the catalytic site in the binding pocket. The disadvantage of this combination method is that when the group at the covalent coupling site is mutated, it will bring obvious drug Tolerated, with higher risk of side effects
In recent years, a new covalent drug design idea has emerged: targeting cysteine ​​at the non-catalytic site in the binding pocket. The advantage of this design idea is that even if the catalytic site is mutated, the covalent coupling site When cysteine ​​is not mutated, it will not bring obvious drug resistance, and the molecular activity is better than that of non-covalent drugs of the same structure, but if there are no amino acid residues in the binding pocket of the target that can form covalent coupling , covalent drugs cannot be designed for this target

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The synthesis of embodiment 1 compound ConA-1

[0048] 1. Synthesis of Intermediate 1

[0049]

[0050] Using LDK378 as raw material (330mg, 0.6mmol), dissolve it in 50mL of methanol, add methyl acrylate (78mg, 0.9mmol), triethylamine (240mg, 2.4mmol), stir at room temperature for 8h, and check the progress of the reaction by TLC. Treatment method: first remove methanol by distillation under reduced pressure, add 150mL ethyl acetate, backwash the organic solution three times with water, remove water with anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography with PE / EA separation system to obtain a white solid. The yield is about 90%.

[0051] 1 H NMR (400MHz, CDCl 3 )δ=9.49(s,1H),8.58(d,J=8.4,1H),8.15(s,1H),7.99(s,1H),7.93(d,J=8.0,1H),7.62(t, J=7.9,1H),7.53(s,1H),7.24(d,J=7.7,1H),6.80(s,1H),4.53(dt,J=12.1,6.0,1H),3.71(s,3H ),3.32–3.21(m,1H),3.06(d,J=9.6,2H),2.77(d,J=6.7,2H),2.72–2.52(m,3H),2.15(s,4H),1.76 (s,4H),1.34(dd...

Embodiment 2

[0064] The synthesis of embodiment 2 compound ConA-2

[0065] 1. Synthesis of intermediate ConA-2M

[0066]

[0067] The preparation method of this intermediate is the same as ConA-1M, the raw material is N-tert-butoxycarbonyl-1,4-butanediamine, and the other raw materials and treatment methods are the same. The yield was 76%.

[0068] 1 H NMR (400MHz, CDCl 3 )δ=6.27(dd, J=17.0,1.6,2H),6.13(dd,J=17.0,10.2,1H),5.62(dd,J=10.2,1.6,1H),4.72(s,1H),3.35 (q,J=6.4,2H),3.13(s,2H),1.62–1.49(m,4H),1.44(s,9H). 13 C NMR (101MHz, CDCl 3 )δ=165.74, 156.23, 130.99, 126.13, 79.27, 39.20, 28.41, 27.71, 26.50. HRMS (DART-TOF) calculated for C 12 h 23 N 2 o 3 [M+H] + m / z243.1709, found 243.1701.

[0069] 2. Synthesis of the target product ConA-2

[0070]

[0071] The preparation method of the target product is the same as ConA-1, the raw material is ConA-2M, and other raw materials and treatment methods are the same. The yield was 67%.

[0072] 1 H NMR (400MHz, CDCl 3 )δ=9.5...

Embodiment 3

[0073] The synthesis of embodiment 3 compound ConA-3

[0074] 1. Synthesis of intermediate ConA-3M

[0075]

[0076] The preparation method of this intermediate is the same as ConA-1M, the raw material is N-tert-butoxycarbonyl-1,6-hexanediamine, and the other raw materials and treatment methods are the same. The yield was 68%.

[0077] 1 H NMR (400MHz, CDCl 3 )δ=6.28(dd, J=17.0,1.4,1H),6.12(dd,J=17.0,10.2,1H),5.62(dd,J=10.2,1.3,1H),3.32(dd,J=13.1, 6.7,2H),3.11(dd,J=12.6,6.2,2H),1.60–1.41(m,13H),1.34(dd,J=8.8,5.6,4H).HRMS(DART-TOF) calculated for C 14 h 26 N 2 o 3 Na[M+Na] + m / z293.1841, found 293.1856.

[0078] 2. Synthesis of target product ConA-3

[0079]

[0080] The preparation method of the target product is the same as ConA-1, the raw material is ConA-3M, and other raw materials and treatment methods are the same. The yield was 67%.

[0081] 1 H NMR (400MHz, CDCl 3 )δ=9.52(s,1H),8.58(d,J=8.4,1H),8.16(s,1H),8.04(d,J=10.3,2H),7.93(dd,J=7.9,1.3,1H ),7.6...

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Abstract

The present invention relates to a design method of covalent drugs and belongs to the technical field of targeted drugs. A technical problem to be solved is providing the design method of the covalentdrugs. The method is primarily to design covalent inhibitors by targeting and binding specific residues at a periphery of a pocket. A main body part of a drug molecule is combined with a binding site, a covalent reaction target head and the specific amino acid residues on the periphery of the pocket form covalent binding, and linker is partially connected with the reaction target head and the main body part. A main structure of the drug molecule is not changed, combination of the main part and the binding site is not influenced, meanwhile, and a covalent bond formed with the specific amino acid residues on the periphery of the pocket can greatly increase binding capacity of the compound molecule and target protein, thereby obtaining lasting and strong biological activity. By using the method, even if no covalent reactive residue exists in the binding pocket, the covalent inhibitors can be developed according to specific amino acids around the pocket, thereby greatly widening design thoughts and application ranges of the covalent drugs.

Description

technical field [0001] The invention relates to a method for designing covalent drugs, belonging to the technical field of targeted drugs. Background technique [0002] Traditional small molecule drugs affect their physiological activity by binding to enzymes or receptor proteins. The typical mode of binding of a drug to a target protein is through non-covalent interactions. Non-covalent interactions, including electrostatic interactions, van der Waals interactions, hydrogen bonds, and hydrophobic interactions can increase the affinity and specificity of ligands to receptors, enzymes, or ion channels. Typically, the maximum binding energy of small molecules to proteins through non-covalent interactions is 6.3 kJ / mol per non-hydrogen atom. However, these non-covalent bindings are reversible and will be competed by endogenous substrates, affecting drug efficacy. [0003] Covalent drugs are a class of drugs that bind to target proteins through covalent interactions to exert ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/58A61K31/506A61P35/00
CPCA61K31/506A61K47/54A61K47/58A61P35/00
Inventor 李锐魏于全
Owner SICHUAN UNIV
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