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Overview

This study has investigated the oral activity, following intragastric administration, of three potent and long-acting peptide-based bradykinin antagonists, HOE-140, B9430, and CP-0597, in the anesthetized rat, using bradykinin-induced hypotension. Two of the three bradykinin antagonists, B9430 and HOE-140, but not CP-0597, were found to be active following intragastric administration, producing dose-dependent (1, 3, and 10 mg/kg) and selective inhibition of bradykinin-induced hypotension. At a dose of 10 mg/kg, the inhibition of bradykinin-induced hypotension occurred within 15 min and lasted for at least 2 h, which was the duration of the experiment. HOE-140 and CP-0597, 10 micrograms/kg i.v., produced significant inhibition of bradykinin-induced responses that lasted for 60 min. B9430, 10 micrograms/kg i.v., produced a significantly greater inhibition than HOE-140 and CP-0597, this inhibition being significant for the duration of the experiment (2 h) compared with saline controls. Considering the close chemical structure of CP-0597 compared with HOE-140 and B9430, it is not clear as to why CP-0597 was inactive via the intragastric route. This is the first demonstration of the oral activity of peptide-based bradykinin antagonists following intragastric administration in the rat.

01 Jun 1997·Canadian Journal of Physiology and PharmacologyQ4 · MEDICINE

In vitro studies of a bradykinin B₁/B₂ antagonist linked to a human neutrophil elastase inhibitor: a heterodimer for the treatment of inflammatory disorders

Q4 · MEDICINE

Article

Author: Zuzack, J. S. ; Gernert, D. L. ; Whalley, E. T. ; Kroona, H. B. ; Burkard, M. R. ; Blodgett, J. K. ; Ross, S. E. ; Dyckes, D. F. ; Leimer, A. H.

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.

01 Jan 1997·Canadian Journal of Physiology and Pharmacology

Oral activity of peptide bradykinin antagonists following intragastric administration in the rat

Author: Stewart, John M. ; Gera, Lajos ; Hanson, Wendy L. ; Whalley, Eric T.

This study has investigated the oral activity, following intragastric administration, of three potent and long-acting peptide-based bradykinin antagonists, HOE-140, B 9430, and CP-0597, in the anesthetized rat, using bradykinin-induced hypotension.Two of the three bradykinin antagonists, B 9430 and HOE-140, but not CP-0597, were found to be active following intragastric administration, producing dose-dependent (1, 3, and 10 mg/kg) and selective inhibition of bradykinin-induced hypotension.At a dose of 10 mg/kg, the inhibition of bradykinin-induced hypotension occurred within 15 min and lasted for at least 2 h, which was the duration of the experimentHOE-140 and CP-0597, 10 μg/kg i.v., produced significant inhibition of bradykinin-induced responses that lasted for 60 min.B 9430, 10 μg/kg i.v., produced a significantly greater inhibition than HOE-140 and CP-0597, this inhibition being significant for the duration of the experiment (2 h) compared with saline controls.Considering the close chem. structure of CP-0597 compared with HOE-140 and B 9430, it is not clear as to why CP-0597 was inactive via the intragastric route.This is the first demonstration of the oral activity of peptide-based bradykinin antagonists following intragastric administration in the rat.

100 Deals associated with Cortech, Inc.

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100 Translational Medicine associated with Cortech, Inc.

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Pipeline

Pipeline Snapshot as of 23 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

CE-1037 ( ELA2 )	Respiratory Distress Syndrome, Adult More	Discontinued
B-9858 ( B1 receptor )	Rheumatoid Arthritis More	Discontinued
CE-2055 ( ELA2 )	Lung Diseases More	Discontinued
CP-0597 ( B2 receptor )	Stroke More	Discontinued
CP-0364 ( B1 receptor x B2 receptor )	Inflammation More	Discontinued