Discovery of Novel and Potent Small-Molecule Inhibitors of NO and Cytokine Production as Antisepsis Agents:  Synthesis and Biological Activity of Alkyl 6-(N-Substituted sulfamoyl)cyclohex-1-ene-1-carboxylate

• Published in: Journal of medicinal chemistry Vol. 48; no. 23; pp. 7457 - 7467
• Main Authors: Yamada, Masami, Ichikawa, Takashi, Ii, Masayuki, Sunamoto, Mie, Itoh, Katsumi, Tamura, Norikazu, Kitazaki, Tomoyuki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.11.2005; Amer Chemical Soc
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiseptics; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Female; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Structure; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Sepsis - metabolism; Sepsis - mortality; Sepsis - prevention & control; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; PATHOGENESIS; INFLAMMATORY RESPONSE SYNDROME; DEFINITIONS; ACTIVATED PROTEIN-C; ENDOTOXIN; SEPTIC SHOCK; INNOVATIVE THERAPIES; MECHANISMS; ORGAN FAILURE; SEVERE SEPSIS; Enantiomer(+); Sulfonamide; Rodentia; Cytokine; In vitro; Biological activity; In vivo; Vertebrata; Mammalia; Mouse; Animal; Nitric oxide; Antiseptic; Production; Carboxylate; Inhibitor; Small molecule; Chemical synthesis; Halogen Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050623t

To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-α, IL-6 and IL-1β] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound (R)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.