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

We found that the most promising compound 4a (R-132811) in this series inhibits the production of the proinflammatory cytokines in vitro and in vivo (e.g., TNFα IC 50 = 0.026 μM, TNFα ID 50 = 0.93 mg/kg). In order to develop a new class of anti-rheumatic drug which inhibits production of proinflammatory cytokines such as TNFα, IL-1β, 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)-1 H-pyrrole (R-132811), achieved the most promising results in various in vitro and in vivo tests including several rheumatoid arthritis models ((i) inhibition of p38α, p38β, p38γ, and p38δ MAP kinases: IC 50 = 0.034, 0.572, >10, and >10 μM, respectively; (ii) inhibition of TNFα, IL-1β, IL-6, and IL-8 production in human whole blood: IC 50 = 0.026, 0.020, 0.88, and 0.016 μM, respectively; (iii) inhibition of LPS induced TNFα, IL-1β and IL-6 production in mice: ID 50 = 0.93, 8.63, and 0.11 mg/kg, po, respectively; (iv) inhibition of anti-collagen antibody-induced arthritis in mice: ID 50 = 2.22 mg/kg, po; (v) inhibition of collagen-induced arthritis in mice: ID 50 = 2.38 mg/kg, po; (vi) prophylactic effect on adjuvant-induced arthritis in rats: ID 50 = 3.1 mg/kg, po; (vii) therapeutic effect on adjuvant-induced arthritis in rats: ID 50 = 4.9 mg/kg, po; (viii) analgesic effect on adjuvant-induced arthritic pain in rats: ID 50 = 2.9 mg/kg, po). As a result, compound 4a was chosen as a candidate for further pre-clinical studies.