Bulky amine analogues of ketoprofen: potent antiinflammatory agents.

Replacement of the carboxyl group of 2-(3-benzoylphenyl)propionic acid (Ketoprofen) with various bulky amines has produced a series of highly active antiinflammatory agents that have reduced intestinal ulcerogenicity and have better therapeutic ratios in the 21-day adjuvant arthritis assay in rats than currently marketed nonsteroidal antiinflammatory drugs. Activity is maintained on reduction of these 2-(3-benzoylphenyl)propyl bulky amines to the corresponding alcohols or methylene analogues, on conversion of the ketone function to a primary amine or oxime, and on introduction of a 4-halo substitutent (Cl or F) on the terminal aromatic ring. Removal of the alpha-CH3 group greatly reduces the antiinflammatory activity of the series. These compounds have been synthesized by the reductive amination of 2-(3-bromophenyl)propionaldehyde with the respective amine followed by lithiation of this product and condensation with the appropriate benzonitrile.

Nivazol: a glucocorticoid in rats with only hypothalamic-pituitary-adrenal-inhibiting activity in primates.

The synthetic steroid nivazol lacks three of the substituents considered to be important for glucocorticoid activity, i.e. the 3-keto, the 11-hydroxy, and the 20-keto groups. Nevertheless, in the rat, nivazol has the activity profile of a glucocorticoid. After treatment of intact female rats with nivazol , the mean weights of the adrenals and thymus were lower than those in the vehicle-treated control group. The results were qualitatively and quantitatively similar to those obtained with methylprednisolone. Thymolysis as well as liver glycogen deposition were seen in adrenalectomized rats treated with nivazol , and eosinopenia and inhibition of carrageenan edema were noted in intact rats. In the rhesus monkey, treatment with nivazol resulted in a marked reduction in circulating cortisol levels and elimination of the diurnal pattern, although a dose 10 times that needed to reduce circulating cortisol levels did not produce eosinopenia or increase fasting blood glucose levels. Both eosinopenia and higher fasting blood glucose levels were seen after treatment with methylprednisolone. Nivazol did not prevent the ACTH-induced increase in circulating cortisol levels nor did it alter circulating aldosterone levels. Therefore, suppression of ACTH is the predominant if not the sole action of nivazol in the primate. Preliminary results in clinical trials suggest a similar activity profile in humans. Therefore, nivazol elicits numerous glucocorticoid activities in the rodent, but only the inhibition of the hypothalamic-pituitary-adrenal axis was observed in the primate. It is of special interest that the inhibition of the hypothalamic-pituitary-adrenal axis occurs without altering circulating aldosterone levels and without evidence of debilitating catabolic activity.