Selective cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents.

A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.

Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors.

The synthesis and activity of a series of 4,5-diarylimidazole analogs are described. One analog had an IC50 of 80 nM, was 6750-selective against COX-1, and demonstrated in vivo potency in the mouse air pouch model.

1,2-Diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2.

Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = > 1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40-80 nm) with excellent selectivity (1200 to > 2500) vs COX-1. Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC50 = 30-120 nm). In vivo testing in the carrageenan-induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED50 of 4.7 mpk.

1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents.

Series of 1,2-diarylimidazoles has been synthesized and found to contain highly potent and selective inhibitors of the human COX-2 enzyme. The paper describes a short synthesis of the target 1,2-diarylimidazoles starting with aryl nitriles. Different portions of the diarylimidazole (I) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC50 = 10-100 nm) and selective (1000-12500) inhibitors of the COX-2 enzyme. The study on the influence of substituents in the imidazole ring established that a CF3 group at position 4 gives the optimum oral activity. A number of the diarylimidazoles showed excellent inhibition in the adjuvant induced arthritis model (e.g., ED50 = 0.02 mpk for 22 and 34). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED50 = 9-30 mpk) and hyperalgesia (ED50 = 11-40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.

Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analogue of misoprostol.

A stereospecific synthesis and the gastric antisecretory and diarrheal activity of a 3E,5Z diene analogue of misoprostol are described. The key intermediate in the synthesis was an alpha chain truncated acetylene that was obtained by a cuprate/enolate capture procedure on the corresponding cyclopentenone. Palladium-catalyzed coupling of the acetylene with methyl 4-iodo-3(E)-butenoate provided the conjugated enyne. Although selective hydrogenation of the enyne with Lindlar catalyst failed, the desired 3E,5Z diene was obtained with P-2 nickel as catalyst. The diene was about 3 times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

Alpha chain unsaturated derivatives of misoprostol.

Misoprostol, a 15-deoxy-16-hydroxy-16-methyl analog of PGE1, is an effective agent for the treatment of peptic ulcer disease. Efforts to impede metabolic degradation of the alpha chain of misoprostol led to the discovery of a second clinical candidate in this series. Enisoprost, a delta 4Z derivative of misoprostol, is more potent as a gastric antisecretory agent and longer acting than misoprostol. These findings prompted further work to determine the effects that two double bonds in the alpha chain might have on the activity profile of misoprostol. The most promising structure in this series was a 1:1 mixture of 3E,5Z and 3Z,5Z dienes which was about three times more potent than misoprostol in inhibiting gastric secretion in dogs, while the separation of the diarrheogenic effect was significantly improved. Chromatographic separation of the mixture was very difficult, but small amounts of each isomer were obtained by HPLC, and preliminary antisecretory studies indicated that most of the activity resided in the 3E,5Z isomer. A stereospecific synthesis of the 3E,5Z isomer was carried out to provide sufficient quantities for complete pharmacological assessment. The 3E,5Z diene was about three times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

Synthesis and antimineralocorticoid activities of some 6-substituted 7 alpha-carboalkoxy steroidal spirolactones.

Several analogues of the previously reported steroidal spirolactone 1a were synthesized. These analogues bear C-6 substituents and include the 6beta-deuterio (1c), the 6beta-bromo (1d), the 6beta-methyl (1e), and the 6alpha-methyl (7) compounds. The 6beta-hydroxy compound 1b, a human and animal metabolite of 1a, was also synthesized. On subcutaneous administration to adrenalectomized rats, all these compounds exhibited the ability to block the effects of administered deoxycorticosterone acetate (DCA) (MED less than or equal to 0.58 mg). Only 7 failed to show anti-DCA effects at the standard test level on oral administration. None was significantly superior in potency to the parent compound 1a.

Mexrenoate potassium: a steroidal aldosterone antagonist and antihypertensive.

Mexrenoate potassium (SC-26714) is a water soluble salt of a steroidal hydroxy acid which has been shown to antagonize the sodium-retaining effects of aldosterone at oral dosages of 1 mg/kg and about 1.8 mg/kg in the dog and rat, respectively. Dose-related natriuretic responses, indexed as a reversal (increases) in the aldosterone-depressed urinary log Na/K ratio, indicated that mexrenoate was between 2.1 (dog) and 4.5 (rat) times as potent as spironolactone. Based on sodium output, in intact rats, mexrenoate was essentially inactive as a diuretic with an estimated potency of less than 0.4% that of hydrochlorothiazide. Diuretic potency was not indicative of antihypertensive potency. In dogs with established hypertension (Page model with the remaining kidney decapsulated and cellophane wrapped) both mexrenoate and spironolactone exhibited equivalent antihypertensive responses. An optimum oral dose of either compound was 5 mg/kg/day. Initial and maximum antihypertensive responses were observed on the 2nd and 5th days of treatment, respectively. Recovery to pretreatment hypertensive levels was observed 72 hours later. Mexrenoate shares with spironolactone the pharmacological characteristics of an aldosterone antagonist.

Synthesis and antimineralocorticoid activities of some 7alpha-cyano and 7alpha-alkoxycarbonylamino steroidal spirolactones.

The synthesis and antimineralocorticoid potencies of several steroidal spirolactones bearing novel nitrogenous substituents in the 7alpha position are reported. These substituents include the cyano, the isocyanato, and the alkoxycarbonylamino groupings. The nitrile 1b and the N-carbomethoxy compound 1h showed good antimineralocorticoid potency (MED less than or equal to 0.79 mg) on subcutaneous administration to adrenalectomized rats.

7alpha-Carboalkoxy steroidal spirolactones as aldosterone antagonists.

A variety of esters of 17-hydroxy-3-oxo-17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid-gamma-lactone (7a) was synthetized in a sequence using the corresponding 3-oxo-4,6-diene (2) as starting material. The methyl (5), ethyl (7c), and isopropyl (7e) esters as well as the C-1 unsaturated methyl ester (8a) showed good oral and subcutaneous activity (MED less than or equal to 0.41 mg). Some general observations on structure-activity relationships are made.