IN-VITRO STUDIES OF A BRADYKININ B-1 B-2 ANTAGONIST LINKED TO A HUMANNEUTROPHIL ELASTASE INHIBITOR - A HETERODIMER FOR THE TREATMENT OF INFLAMMATORY DISORDERS/

Inflammatory disorders typically have a complex etiology and involve a multitude of inflammatory mediators, and hence, a polytherapeutic app roach to these diseases would seem appropriate. In certain chronic inf lammatory conditions, we believe that bradykinin (BK) and human neutro phil elastase (HNE) are cooperatively involved. We have previously syn thesized compounds with inhibitory activity toward both the BK B-2 rec eptor and HNE. The present study describes single compounds designed t o incorporate HNE inhibitory activity and BK B-1 and B-2 antagonist ac tivity. A proprietary HNE inhibitor (HNEI, CP-955) was directly linked via amide bond formation to a peptide-based combined BK B-1/B-2 antag onist (B-9430). Three compounds were made using different linking posi tions in the antagonist peptide. For all compounds, B-1 and B-2 recept or binding in human cloned receptors was at least 10-fold less than th at of B-9430, whereas in the in vitro guinea pig ileum B-2 receptor fu nctional assay, the compounds had potencies equivalent to B-9430. Comp ound I was found to have a fourfold increase in HNEI activity compared with CP-955, whereas compounds II and III were inactive. These data c learly demonstrate that it is possible to retain BK B-1/B-2 receptor a ntagonist and HNE activity in a heterodimer.