Structure-activity studies of 4,6-disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives with analgesic and antiinflammatory activities.

4,6-Disubstituted 2-(morpholinocarbonyl)furo[3,2-b]indole derivatives showed analgesic and antiinflammatory activities when assayed by the acetic acid writhing test in mice and the carrageenin edema test in rats. To understand how the substituents affect the biological activities, the quantitative structure-activity relationships (QSAR) of 38 compounds were analyzed using the adaptive least-squares method (ALS method). The resulting QSAR suggested that some chemical modifications of 4,6-disubstituted furo[3,2-b]indole derivatives would improve their biological activities. Thus, 15 additional compounds were synthesized to reinforce and confirm the correlation. Among these compounds, particularly 4-(2-ethylhexanoyl)-2-(morpholinocarbonyl)-6-(trifluoromethy l) furo[3,2-b]indole showed pronounced biological activities. This compound gave a pharmacological activity spectrum similar to that of tiaramide but exhibited much higher potency.

Pharmacological studies of furo [3,2-b]indole derivatives. II. Analgesic effect of FI-302, N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-furo[3,2-b]ind ole-2-carboxamide, in experimental animals.

FI-302, N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-furo[3,2-b]indol e-2-carboxamide, is a new non-steroidal anti-inflammatory compound. The analgesic effect of FI-302 was investigated in comparison with those of non-steroidal anti-inflammatory drugs (NSAIDs). In the tail pressure, hot plate and D'Amour and Smith methods, FI-302 showed a potent analgesic effect, its efficacy being about 2 to 7 times greater than those of aminopyrine, mepirizole and tiaramide. On the other hand, in these methods, aspirin, ibuprofen and phenylbutazone had little or no effect. FI-302 showed a potent inhibitory effect on the vocalization response produced by electrical stimulation. Moreover, the analgesic effect of FI-302 after intracerebroventricular injection was about 58 to 278 times more potent than those of tiaramide and ibuprofen, and about 1/6 that of morphine. However, the analgesic effect of FI-302 was not antagonized by levallorphan. From these results, it appears that FI-302 has potent analgesic effects which may be produced by both peripheral and central mechanisms, but it is a non-narcotic compound. Consequently, FI-302 should be suitably applicable for clinical purposes.

[Effect of various types of analgesic drugs on an experimental model of chronic inflammatory pain in mice].

We attempted to develop an experimental model of chronic inflammatory pain in mice. The mice were injected intradermally at the base of the tail with various kinds of irritants (yeast, carrageenin, mustard and adjuvant). The pain threshold was measured by the pressure method every 60 min for 5 hr and once a day at the same time throughout the experimental period. The group of 10% yeast-injected mice exhibited the most intensive hyperalgesia. The analgesic effect of various types of analgesic drugs were studied, comparing the effects in normal mice and various kinds of irritants-induced hyperalgesia mice. It was demonstrated by observing ED50 values that nonsteroidal antiinflammatory drugs (NSAIDs), narcotic analgesic drugs and agonist/antagonist type of analgesic drugs were effective, but CNS-acting drugs were ineffective in yeast hyperalgesia mice. In comparison with yeast hyperalgesia mice, larger doses of analgesic drugs were required in normal mice and other irritants-treated mice. Especially, acidic NSAIDs were more effective in yeast hyperalgesia mice than normal mice. It was suggested that acidic NSAIDs specifically inhibit inflammatory pain. Moreover, yeast hyperalgesia mice are useful for the quantitative measurement of analgesic drugs.

Pharmacological studies of furo [3,2-b] indole derivatives. I. Analgesic, anti-pyretic and anti-inflammatory effects of FI-302, N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-furo [3,2-b]indole-2-carboxamide, in experimental animals.

The analgesic, anti-pyretic and anti-inflammatory effects of FI-302, N-(3-piperidinopropyl)-4-methyl-6-trifluoromethyl-furo [3,2-b]indole-2-carboxamide, a newly synthesized tricyclic compound, were investigated in comparison with those of nonsteroidal anti-inflammatory drugs (NSAIDs). FI-302 showed potent analgesic and antipyretic effects in the various models used. FI-302 showed an inhibitory effect on acute inflammatory response such as carrageenin-induced edema, but did not show any effect on chronic inflammatory response such as cotton pellet granuloma. These effects of FI-302 were about 2 to 7 times more potent than those of non-acidic NSAIDs such as mepirizole and tiaramide. Moreover, FI-302 had little or no ulcerogenic activity. From these results, it is conceivable that the spectrum of FI-302's activities is similar to those of non-acidic NSAIDs such as mepirizole and tiaramide. These results suggest that FI-302 is a new non-ulcerogenic anti-inflammatory compound, and should be suitably applicable for clinical purposes.

[The analgesic effects of non-steroidal anti-inflammatory drugs on acetylcholine-induced writhing in mice].

The experimental conditions of acetylcholine (ACh)-induced writhing were investigated, and the analgesic effects of non-steroidal anti-inflammatory drugs (NSAIDs) on ACh-induced writhing were investigated in comparison with those on other writhings. Mice injected (i.p.) with more than 5 mg/kg of ACh showed the writhing response, and the number of writhes were almost equal in all mice. Therefore, the analgesic effects were evaluated as follows: NSAIDs were administered orally 30 min before the ACh injection (5 mg/kg, i.p.), the number of writhes were counted in each mouse during a period of 10 min following the ACh injection, and mice that did not show any writhing responses were regarded as positive for the analgesic activity. The analgesic effects of NSAIDs showing the inhibitory effect on prostaglandins (PGs) biosynthesis were more potent than those in other writhing tests. The ED50 values in the ACh-induced writhing were highly correlated with the IC50 values in the inhibitory effects on PGs biosynthesis (r = 0.81, P less than 0.01) and with the ED50 values in the anti-castor oil diarrhoea (r = 0.93, P less than 0.01). Moreover, the ED50 values of acidic NSAIDs in ACh-induced writhing were also highly correlated with the clinical doses (r = 0.90, P less than 0.001). These results suggest that the ACh-induced writhing method should be useful for the evaluation of the analgesic effects of acidic NSAIDs, and the analgesic effects on the ACh-induced writhing are related to their inhibitory effects on PGs biosynthesis.

[Anti-inflammatory, analgesic and anti-pyretic activities of a new anti-inflammatory compound, 2-[4-(3-methyl-2-butenyl)phenyl] propionic acid (TA), in experimental animals].

Anti-inflammatory, analgesic and anti-pyretic activities of orally administered TA were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice, carrageenin-induced hind paw edema in rats and ultra-violet ray-induced erythema in guinea pigs, TA produced a dose related inhibition at doses of 40-160 mg/kg, 10-40 mg/kg and 10-40 mg/kg, respectively. TA produced no inhibition against histamine-induced vascular permeability even at a dose of 200 mg/kg in rats. Cotton pellet-induced granuloma and adjuvant-induced arthritis in rats were significantly inhibited by repeated administration of TA at a dose of 50 mg/kg/day for 6 days and 25 mg/kg/day for 6 days, respectively. TA showed a dose related analgesic effect at a dose of 50-200 mg/kg in acetic acid writhing, Randall-Selitto and adjuvant arthritic pain methods. A high dose of TA was needed to produce an analgesic effect in the pressure method using mice. TA produced an anti-pyretic effect against the pyrexia induced by yeast in rats. On the other hand, TA showed no effect against normal body temperature in rats. These results suggest that anti-inflammatory, analgesic and anti-pyretic activities of TA are generally a little weaker than those of ibuprofen, and the mode of action of TA is similar to that of a typical acidic non-steroidal anti-inflammatory drug such as ibuprofen, indomethacin or phenylbutazone. The ulcerogenic activity of TA was about 2 and 4 times weaker than that of ibuprofen in rats and mice, respectively. TA showed a protective effect against gastric necrosis induced by HCl.(ABSTRACT TRUNCATED AT 250 WORDS)

[Anti-inflammatory activity of a non-steroidal anti-inflammatory agent, oxaprozin, in experimental models].

Anti-inflammatory activity and mode of action of oxaprozin, a new non-steroidal anti-inflammatory agent, were investigated in experimental animal models and in vitro tests. Anti-inflammatory potency of oxaprozin was almost equal to that of aspirin in acetic acid vascular permeability, carrageenin hind paw edema, cotton pellet granuloma and adjuvant arthritis tests in rats. On the other hand, in mice, oxaprozin was more potent than aspirin, ibuprofen and phenylbutazone, and it was as potent as sulindac and fenbufen in acetic acid vascular permeability and carrageenin hind paw edema tests. In adrenalectomized rats, the anti-edema activity of oxaprozin in the carrageenin hind paw edema test was the same as that in intact rats. Oxaprozin inhibited erythema formation induced by ultra-violet rays in guinea pigs. The inhibitory potency of oxaprozin against prostaglandin E2 biosynthesis in vitro was equal to that of ibuprofen. Oxaprozin showed a concentration-dependent inhibition of heat-induced denaturation of bovine serum albumin and lysis of rabbit erythrocytes in vitro. However, oxaprozin did not inhibit rat hind paw edemas induced by dextran, formalin and serotonin. It was suggested from these results that the mode of action of oxaprozin is similar to those of other acidic non-steroidal anti-inflammatory drugs. Ulcerogenicity of oxaprozin was weaker than those of phenylbutazone and aspirin in rats. Species differences in the metabolic rate of oxaprozin were shown. The blood concentration of oxaprozin in rats is extremely low because the metabolic rate of oxaprozin is rapid in rats. Therefore, in rats, oxaprozin exhibited a weak anti-inflammatory effect. However, in mice, oxaprozin had a low metabolic rate, and the effect of oxaprozin was as potent as sulindac and fenbufen. The elimination half-life of oxaprozin is extended, 49 to 69 hr, in humans. It was suggested from these findings that oxaprozin is a potent and long acting anti-inflammatory drug in clinical use.

[The analgesic and antipyretic effects of a non-steroidal anti-inflammatory drug, oxaprozin, in experimental animals].

The analgesic and antipyretic effects of oxaprozin were investigated in comparison with those of indomethacin, ibuprofen, phenylbutazone and aspirin. On the various writhing tests in mice, the analgesic effect of oxaprozin was about 2 to 9 times more potent than those of ibuprofen, phenylbutazone and aspirin. On the other hand, the analgesic and antipyretic effects of oxaprozin in rats were roughly equivalent to those of aspirin, but less effective than those of the other drugs tested. On the urate synovitis test in dogs, only oxaprozin showed a prophylactic effect. Therefore, The effect of oxaprozin in mice and dogs was more potent than ibuprofen, phenylbutazone and aspirin. The metabolic rate of oxaprozin in rats is 3.5 and 7.2 times more rapid than in mice and dogs, respectively, and its blood level in rats is low. Moreover, the biological half-life of oxaprozin is 39 to 43 hr and 49 to 69 hr in dogs and humans, respectively. From these results, it is suggested that oxaprozin is more potent than ibuprofen, phenylbutazone and aspirin, and in clinical use, it is a long acting anti-inflammatory drug.