Romazarit: a potential disease-modifying antirheumatic drug.

The synthesis of a series of substituted heterocyclic alkoxypropionic acids is described. They were evaluated for antiinflammatory effects in two animal models of chronic inflammation; adjuvant arthritis and type II collagen arthritis in the rat. The desired profile of biological activity was characterized by the reduction of inflammation with the coincident restoration toward normal levels of the biochemical markers (acute phase proteins) associated with the inflammatory response, an effect that was not shared by classical nonsteroidal antiinflammatory agents. Romazarit, (Ro 31-3948, 7), 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropio nic acid, was selected for further evaluation. In contrast to NSAIDs, romazarit was inactive in animal models of acute inflammation, and furthermore it did not inhibit the cyclooxygenase enzyme in vitro or in vivo. Inhibition of interleukin-1-mediated events in vitro has been observed.

Beta-adrenoceptor activity of the stereoisomers of the bufuralol alcohol and ketone metabolites.

The stereoisomers of 2-[(tert-butylamino)methyl]-7-methyl-2,7-benzofurandimethanol (2) and 2-[2-(tert-butylamino)-1-hydroxyethyl]-7-benzofuranyl methyl ketone (3), the alcohol and ketone metabolites of bufuralol, have been prepared and examined for beta-adrenoceptor activity in rats. All the stereoisomers with the S configuration hydroxylamine side chain showed potent beta 2-antagonist activity comparable to (S)-bufuralol (1a). In contrast, a wide range of antagonist potencies was observed at the beta 1-receptor; only alcohol diastereomer 9a was more active than 1a. This suggests that the shape of the 7-substituent in these benzofurans influences the degree of interaction with the beta 1-receptor much more than with the beta 2-receptor. Partial beta 1-agonist activity was associated not only with all the stereoisomers with the S configuration hydroxylamine side chain but also with some of the R configuration derivatives, especially (R)-ketone 3b. The results suggest that the margin of difference in beta-adrenoceptor activity between compounds epimeric at the hydroxylamine side chain can be significantly influenced by a suitable substituent in the aromatic nucleus.

Bufuralol, a new beta-adrenoceptor blocking agent. Part 1: synthesis and structure-activity studies in a series of benzofuran-2-ethanolamines.

The synthesis and resolution of a new beta-adrenoceptor blocking agent, 1-(7-ethylbenzofuran-2-yl)-2-tert.-butylamino-1-hydroxyethane (bufuralol) are described. Structure-activity studies leading to selection of the title compound are discussed.