title: In vitro studies of a bradykinin B1/B2 antagonist linked to a human neutrophil elastase inhibitor; a heterodimer for the treatment of inflammatory disorders.
abstract: Inflammatory disorders typically have a complex etiology and involve a multitude of inflammatory mediators, and hence, a polytherapeutic approach to these diseases would seem appropriate. In certain chronic inflammatory conditions, we believe that bradykinin (BK) and human neutrophil elastase (HNE) are cooperatively involved. We have previously synthesized compounds with inhibitory activity toward both the BK B2 receptor and HNE. The present study describes single compounds designed to incorporate HNE inhibitory activity and BK B1 and B2 antagonist activity. A proprietary HNE inhibitor (HNEI, CP-955) was directly linked via amide bond formation to a peptide-based combined BK B1/B2 antagonist (B-9430). Three compounds were made using different linking positions in the antagonist peptide. For all compounds, B1 and B2 receptor binding in human cloned receptors was at least 10-fold less than that of B-9430, whereas in the in vitro guinea pig ileum B2 receptor functional assay, the compounds had potencies equivalent to B-9430. Compound I was found to have a fourfold increase in HNEI activity compared with CP-955, whereas compounds II and III were inactive. These data clearly demonstrate that it is possible to retain BK B1/B2 receptor antagonist and HNE activity in a heterodimer.
authors.affiliation: Cortech Inc., Denver, CO 80221, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Leimer
authors.forename: H B
authors.initials: HB
authors.lastname: Kroona
authors.forename: J K
authors.initials: JK
authors.lastname: Blodgett
authors.forename: E T
authors.initials: ET
authors.lastname: Whalley
authors.forename: S E
authors.initials: SE
authors.lastname: Ross
authors.forename: M R
authors.initials: MR
authors.lastname: Burkard
authors.forename: J S
authors.initials: JS
authors.lastname: Zuzack
authors.forename: D L
authors.initials: DL
authors.lastname: Gernert
authors.forename: D F
authors.initials: DF
authors.lastname: Dyckes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D019272:Leukocyte Elastase