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Tetrahydropyridine derivatives with inhibitory activity on the production of proinflammatory cytokines: part 3.

Abstract
In order to develop a new class of anti-rheumatic drug which inhibits production of proinflammatory cytokines such as TNFalpha, IL-1beta, IL-6, and IL-8, a series of 3-pyridylpyrrole derivatives possessing a bicyclic tetrahydropyridine moiety at the 4-position of the pyrrole ring were synthesized and their pharmacological activities were evaluated. The derivatives were found to have potent inhibitory activities on the production of the cytokines both in vitro and in vivo. Among them, compound 4a, (S)-2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38alpha, p38beta, p38gamma, and p38delta MAP kinases: IC(50)=0.034, 0.572, >10, and >10 microM, respectively; (ii) inhibition of TNFalpha, IL-1beta, IL-6, and IL-8 production in human whole blood: IC(50)=0.026, 0.020, 0.88, and 0.016 microM, respectively; (iii) inhibition of LPS induced TNFalpha, IL-1beta and IL-6 production in mice: ID(50)=0.93, 8.63, and 0.11 mg/kg, p.o., respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID(50)=2.22 mg/kg, p.o.; (v) inhibition of collagen-induced arthritis in mice: ID(50)=2.38 mg/kg, p.o.; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID(50)=3.1 mg/kg, p.o.; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID(50)=4.9 mg/kg, p.o.; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID(50)=2.9 mg/kg, p.o.). As a result, compound 4a was chosen as a candidate for further pre-clinical studies.
AuthorsAkira Nakao, Nobuyuki Ohkawa, Takayoshi Nagasaki, Takashi Kagari, Hiromi Doi, Takaichi Shimozato, Shigeru Ushiyama, Kazumasa Aoki
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 16 Pg. 4774-8 (Aug 15 2010) ISSN: 1464-3405 [Electronic] England
PMID20637613 (Publication Type: Journal Article)
CopyrightCrown Copyright 2010. Published by Elsevier Ltd. All rights reserved.
Chemical References
  • 2-(4-fluorophenyl)-4-(1,2,3,5,6,8a-hexahydroindolizin-7-yl)-3-(pyridin-4-yl)-1H-pyrrole
  • Antirheumatic Agents
  • Cytokines
  • Indolizines
  • Interleukin-1beta
  • Interleukin-6
  • Interleukin-8
  • Pyridines
  • Pyrroles
  • Tumor Necrosis Factor-alpha
Topics
  • Animals
  • Antirheumatic Agents (chemistry, pharmacology)
  • Arthritis, Experimental (chemically induced, drug therapy)
  • Cytokines (antagonists & inhibitors, metabolism)
  • Humans
  • Indolizines (chemical synthesis, chemistry, pharmacology)
  • Interleukin-1beta (antagonists & inhibitors, metabolism)
  • Interleukin-6 (antagonists & inhibitors, metabolism)
  • Interleukin-8 (antagonists & inhibitors, metabolism)
  • Mice
  • Pyridines (chemistry, pharmacology)
  • Pyrroles (chemical synthesis, chemistry, pharmacology)
  • Rats
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)

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