SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, AND PHARMACOLOGICAL EVALUATION OF PYRROLO[3,2,1-IJ]QUINOLINE DERIVATIVES - POTENT HISTAMINE AND PLATELET-ACTIVATING-FACTOR ANTAGONISM AND 5-LIPOXYGENASE INHIBITORY PROPERTIES - POTENTIAL THERAPEUTIC APPLICATION IN ASTHMA

A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized and evaluated for their in vitro and in vivo activities against histamine , platelet activating factor (PAF), and leukotrienes which are recogni zed to be of importance in asthma. The structure-activity relationship studies have shown that the optimum moiety on the 1-position of the p yrroloquinoline nucleus is a 2-[4-(4-methyl-2-pyridinyl)-1-piperazinyl ]ethyl chain in conjunction with a methyl group on the 2-position for potent antagonism of both histamine and PAF. The introduction of subst ituents on the 8- and 4-positions was also investigated in order to in crease the potency of 5-lipoxygenase inhibition while retaining or imp roving the activities against histamine and PAF. This series is exempl ified by -5,6-dihydro-8-hydroxy-2-methyl-1-[2-[4-(4-methyl- 1-piperazi nyl]ethyl]-4H-pyrrolo[3,2,1-ij]quinoline (24, KC 11404) which was foun d to be active against all three of the selected mediators. Compound 2 4 was found to be orally active in guinea pig models against the hista minic phase of antigen-induced bronchospasm and PAF-induced bronchocon striction (ED(50) = 1.9 and 2.1 mu mol/kg, respectively). When tested against the leukotriene-dependent phase of the antigen-induced broncho constriction, compound 24 showed the same potency as zileuton.