115363-11-6Relevant articles and documents
The Stone Guest: How Does pH Affect Binding Properties of PD-1/PD-L1 Inhibitors?
Riccio, Alessandra,Coletti, Alice,Dolciami, Daniela,Mammoli, Andrea,Cerra, Bruno,Moretti, Sonia,Gioiello, Antimo,Ferlin, Simone,Puxeddu, Efisio,Macchiarulo, Antonio
, p. 568 - 577 (2021)
The interaction between programmed cell death-1 (PD-1) and its ligand PD?L1 activates a coinhibitory signal that blocks T-cell activation, promoting the immune escape process in the tumor microenvironment. Development of monoclonal antibodies targeting and inhibiting PD-1/PD?L1 interaction as anticancer immunotherapies has proved successful in multiple clinical settings and for various types of cancer. Notwithstanding, limitations exist with the use of these biologics, including drug resistance and narrow therapeutic response rate in a majority of patients, that demand for the design of more efficacious small molecule-based immunotherapies. Alteration of pH in the tumor microenvironment is a key factor that is involved in promoting drug resistance, tumor survival and progression. In this study, we have investigated the effect of pH shifts on binding properties of distinct classes of PD?L1 inhibitors, including macrocyclic peptide and small molecules. Results expand structure-activity relationships of PD?L1 inhibitors, providing insights into structural features and physicochemical properties that are useful for the design of ligands that may escape a drug resistance mechanism associated to variable pH conditions of tumor microenvironment.
Synthesis method of key intermediate of PD-I ligand
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Paragraph 0036-0039, (2021/10/05)
The invention provides a synthesis method of a key intermediate of a PD-I ligand. The synthesis method comprises the following steps: preparing an intermediate 5 from a compound 2, and directly dissolving the intermediate 5 in a solvent to obtain a compound 6; reacting a compound 3 with a compound 4 to obtain a compound 7; refluxing the compound 7, concentrating to dry, dissolving in tetrahydrofuran, and dropwise adding into a solution containing the compound 6 and n-butyllithium; after the reaction is finished, obtaining a compound 8; adding lithium borohydride into the dry tetrahydrofuran containing the compound 8, stirring, quenching, extracting and the like to obtain a crude product, and purifying to obtain a compound 9; mixing the compound 9 and manganese dioxide in toluene, cooling the reaction liquid, filtering, concentrating the filtrate, and purifying to obtain a compound 10; adding the compound 10 and a Lawesson reagent into dry tetrahydrofuran, and heating to reflux until the reaction is completed; and concentrating purifying the reaction liquid, and and to obtain a compound 1. According to the route, only one step of metal catalysis is used, and the step is far away from a final compound, so that metal residues in medicine molecules are greatly reduced.
Phenyl-substituted five-membered heterocyclic compounds as well as preparation method, application and pharmaceutical composition thereof
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Paragraph 0051-0056, (2020/10/14)
The invention discloses immune checkpoint inhibitor phenyl-substituted five-membered heterocyclic compounds capable of blocking a PD-1/PD-L1 signal path as well as a preparation method, application and a pharmaceutical composition thereof. The phenyl-substituted five-membered heterocycle compounds are shown as a formula I. The phenyl-substituted five-membered heterocycle compounds or pharmaceutically acceptable salts, racemates, optical isomers or solvent compounds thereof are disclosed.
