- Diarylureas Containing 5-Membered Heterocycles as CB1 Receptor Allosteric Modulators: Design, Synthesis, and Pharmacological Evaluation
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Allosteric modulators have attracted significant interest as an alternate strategy to modulate CB1 receptor signaling for therapeutic benefits that may avoid the adverse effects associated with orthosteric ligands. Here we extended our previous structure-activity relationship studies on the diarylurea-based CB1 negative allosteric modulators (NAMs) by introducing five-membered heterocycles to replace the 5-pyrrolidinylpyridinyl group in PSNCBAM-1 (1), one of the first generation CB1 allosteric modulators. Many of these compounds had comparable potency to 1 in blocking the CB1 agonist CP55,940 stimulated calcium mobilization and [35S]GTP-γ-S binding. Similar to 1, most compounds showed positive cooperativity by increasing [3H]CP55,940 binding, consistent with the positive allosteric modulator (PAM)-antagonist mechanism. Interestingly, these compounds exhibited differences in ability to increase specific binding of [3H]CP55,940 and decrease binding of the antagonist [3H]SR141716. In saturation binding studies, only increases in [3H]CP55,940 Bmax, but not Kd, were observed, suggesting that these compounds stabilize low affinity receptors into a high affinity state. Among the series, the 2-pyrrolyl analogue (13) exhibited greater potency than 1 in the [35S]GTP-γ-S binding assay and significantly enhanced the maximum binding level in the [3H]CP5,5940 binding assay, indicating greater CB1 receptor affinity and/or cooperativity.
- Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,German, Nadezhda,Langston, Tiffany L.,Farquhar, Charlotte E.,Kenakin, Terry P.,Wiley, Jenny L.,Thomas, Brian F.,Zhang, Yanan
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p. 518 - 527
(2018/10/02)
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- DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS
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The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
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Paragraph 69; 72; 110
(2018/12/02)
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- Design, synthesis and biological evaluation of N-arylphenyl-2,2- dichloroacetamide analogues as anti-cancer agents
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Our earlier research has shown that N-phenyl-2,2-dichloroacetamide analogues had much higher anti-cancer activity than the lead compound sodium dichloroacetate (DCA). In this current study, a variety of N-arylphenyl-2,2- dichloroacetamide analogues were synthesized via Suzuki coupling reaction and their anti-cancer activity was evaluated. The results showed that N-terphenyl-2,2-dichloroacetamide analogues had satisfactory anti-cancer activity. Among them, N-(3,5-bis(benzo[d][1,3]dioxol-5-yl)phenyl)-2,2- dichloroacetamide (6 k) had an IC50 of 2.40 μM against KB-3-1 cells, 1.04 μM against H460 cells and 1.73 μM against A549 cells.
- Li, Tianwen,Yang, Yongchong,Cheng, Changmei,Tiwari, Amit K.,Sodani, Kamlesh,Zhao, Yufen,Abraham, Ioana,Chen, Zhe-Sheng
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supporting information
p. 7268 - 7271
(2013/01/15)
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- Structural modifications of salicylates: Inhibitors of human CD81-receptor HCV-E2 interaction
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Starting point of the present paper was the result of a virtual screening using the open conformation of the large extracellular loop (LEL) of the CD81-receptor (crystal structure: PDB-ID: 1G8Q). After benzyl salicylate had been experimentally validated to be a moderate inhibitor of the CD81-LEL-HCV-E2 interaction, further optimization was performed and heterocyclic-substituted benzyl salicylate derivatives were synthesized. The compounds were tested for their ability to inhibit the interaction of a fluorescence-labeled antibody to CD81-LEL using HUH7.5 cells. No compound showed an increase concerning the inhibition of the protein-protein interaction compared to benzyl salicylate.
- Holzer, Marcel,Ziegler, Sigrid,Neugebauer, Alexander,Kronenberger, Bernd,Klein, Christian D.,Hartmann, Rolf W.
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experimental part
p. 478 - 484
(2009/04/04)
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- Method for treating neoplasia with amino or pyridylamino cyclobutene derivatives
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A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to amino or pyridylamino cyclobutane derivatives.
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