Monocyclic l-Nucleosides with Type 1 Cytokine-Inducing Activity

• Published in: Journal of medicinal chemistry Vol. 43; no. 5; pp. 1019 - 1028
• Main Authors: Ramasamy, Kanda S, Tam, Robert C, Bard, Josie, Averett, Devron R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.03.2000; Amer Chemical Soc
• Subjects: Adjuvants, Immunologic - chemical synthesis; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Chemistry, Medicinal; Cytokines - metabolism; Enzyme-Linked Immunosorbent Assay; Humans; Immunomodulators; In Vitro Techniques; Interferon-gamma - metabolism; Interleukin-2 - metabolism; Life Sciences & Biomedicine; Medical sciences; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Ribavirin - chemical synthesis; Ribavirin - chemistry; Ribavirin - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - metabolism; CELLS; INTERFERON; PROFILES; ENANTIOMERS; DOUBLE-BLIND; RIBAVIRIN; HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-B; ANTIVIRAL ACTIVITIES; LYMPHOCYTES-T; Immunomodulator; Cytokine; L stereoisomer; Triazole derivatives; Amides; Nucleoside; Drift; Chemical synthesis; In vitro; Biological activity; Ribavirin; Dose activity relation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9905514

A series of 1,2,4-triazole l-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-β-l-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-β-l-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided compounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.