Design, synthesis and biological studies of a library of NK1-Receptor Ligands Based on a 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyran core: Switch from antagonist to agonist effect by chemical modification

• Published in: European journal of medicinal chemistry 2017-09, Vol.138, p.644-660
• Main Authors: Recio, Rocío, Vengut-Climent, Empar, Mouillac, Bernard, Orcel, Hélène, López-Lázaro, Miguel, Calderón-Montaño, José Manuel, Álvarez, Eleuterio, Khiar, Noureddine, Fernández, Inmaculada
• Format: Article
• Language: English
• Subjects: 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyran; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; GPCR; Humans; Ligands; Molecular Structure; Neurokinin-1 Receptor Antagonists - chemical synthesis; Neurokinin-1 Receptor Antagonists - chemistry; Neurokinin-1 Receptor Antagonists - pharmacology; Non-peptide NK1 receptor agonists; Non-peptide NK1 receptor antagonists; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Receptors, Neurokinin-1 - agonists; Receptors, Neurokinin-1 - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.056

A library of 5-arylthiosubstituted 2-amino-4,6-diaryl-3-cyano-4H-pyrans has been synthesized as a new family of non-peptide NK1 receptor ligands by a one-pot cascade process. Their biological effects via interaction with the NK1 receptor were experimentally determined as percentage of inhibition (for antagonists) and percentage of activation (for agonists), compared to the substance P (SP) effect, in IPone assay. A set of these amino compounds was found to inhibit the action of SP, and therefore can be considered as a new family of SP-antagonists. Interestingly, the acylation of the 2-amino position causes a switch from antagonist to agonist activity. The 5-phenylsulfonyl-2-amino derivative 17 showed the highest antagonist activity, while the 5-p-tolylsulfenyl-2-trifluoroacetamide derivative 20R showed the highest agonist effect. As expected, in the case of the 5-sulfinylderivatives, there was an enantiomeric discrimination in favor of one of the two enantiomers, specifically those with (SS,RC) configuration. The anticancer activity studies assessed by using human A-549 lung cancer cells and MRC-5 non-malignant lung fibroblasts, revealed a statistically significant selective cytotoxic effect of some of these 2-amino-4H-pyran derivatives toward the lung cancer cells. These studies demonstrated that the newly synthesized 4H-pyran derivatives can be used as a starting point for the synthesis of novel SP-antagonists with higher anticancer activity in the future. [Display omitted] •A new family of NK1 ligands based on a 2-amino-4H-pyran structure was synthesized.•The sulfone 17 represented the lead compound for the design of new NK1 antagonists.•The sulfoxides showed a chiral discrimination in favor of the (SS,RC) enantiomer.•The acylation of the 2-amine position causes a switch from antagonist to agonist.•Some derivatives showed a significant selective cytotoxicity against lung cancer cells.