Synthesis of a series of sulfinic acid analogs of GABA and evaluation of their GABAB receptor affinities.

A series of gamma-aminobutyric acid (GABA) 1 analogs was prepared in which the carboxylic acid group of GABA was replaced with a sulfinic acid group and their affinity for the GABAB receptor investigated.

Synthesis and structure-activity studies of a series of 7 alpha-halogeno corticosteroids.

The preparation and topical antiinflammatory potencies of a series of 7 alpha-halogeno-16-substituted-prednisolone derivatives are described. The 7 alpha-chloro, 7 alpha-bromo, and 7 alpha-iodo corticosteroids were obtained by addition of hydrogen halide to the 6,7-dehydro compounds. The extent of addition of HCl varied with substitution at C-11, while no addition of HF was observed at all. The 7 alpha-fluoro corticosteroids were prepared by reaction of the appropriate 7 beta-hydroxy compounds with N,N-diethyl(2-chloro-1,1,2-trifluoroethyl)amine. The 7 beta-hydroxy steroids were obtained, in turn, from the 6,7-dehydro compounds via the 6 beta,7 beta-dihydroxy derivatives. Antiinflammatory potencies were measured in mice by the Tonelli croton oil ear assay. The greatest effect of a 7 alpha-halogen was observed in the 16 alpha-methylprednisolone series, where 7 alpha-chloro and 7 alpha-bromo substitution increased potency 2.5- to 3.5-fold. Compounds 4b and 5b were equipotent to betamethasone dipropionate. 7 alpha-Halogen substitution in other series produced more variable effects and sometimes led to a reduction of antiinflammatory potency.

The influence of esterification on the topical antiinflammatory activity of 7 alpha-chloro- and 7 alpha-bromo-16 alpha-methylprednisolones.

The effect on topical antiinflammatory potency of altering the ester functions of 7-halogenocorticosteroids was examined. Highest potencies for both 7 alpha-chloro- and 7 alpha-bromo-16 alpha-methylprednisolones were generally achieved through diesterification at the 17- and 21-positions. However, among these diesters, structure seems to be more important for topical potency than lipophilicity.

A novel class of potent topical antiinflammatory agents: 17-benzoylated, 7 alpha-halogeno substituted corticosteroids.

As part of continued efforts in the synthesis of structurally novel corticosteroids, a number of 17 alpha-benzoylated, 7 alpha-halogeno substituted prednisolones were tested for topical antiinflammatory activity. 7 alpha-Chloro, 7 alpha-bromo, and 7 alpha-iodo corticosteroids were synthesized by hydrogen halide addition to 1,4,6-triene-3-ones. The 7 alpha-fluoro substituted steroid was obtained by reaction of the appropriate 7 beta-hydroxy compound with N,N-diethyl(2-chloro-1,1,2-trifluoroethyl)amine. Antiinflammatory potencies were obtained using a croton oil-induced inflammation in the ears of mice. In this assay the greatest effect of a 7 alpha-halogen was observed in the 16 alpha-methylprednisolone series, where 7 alpha-fluoro and 7 alpha-bromo substitution yielded corticosteroids with topical potencies significantly higher than those of the corresponding 17,21-dipropionate analogs. Surprisingly, little potency enhancement due to 7 alpha-halogenation was discerned in the 16 beta-methylprednisolone series.