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.