Novel, selective indole-based ECE inhibitors: lead optimization via solid-phase and classical synthesis

Michael Brands; Jens-Kerim Ergüden; Kentaro Hashimoto; Dirk Heimbach; Christian Schröder; Stephan Siegel; Johannes-Peter Stasch; Stefan Weigand

doi:10.1016/j.bmcl.2005.06.085

Novel, selective indole-based ECE inhibitors: lead optimization via solid-phase and classical synthesis

Bioorg Med Chem Lett. 2005 Oct 1;15(19):4201-5. doi: 10.1016/j.bmcl.2005.06.085.

Authors

Michael Brands¹, Jens-Kerim Ergüden, Kentaro Hashimoto, Dirk Heimbach, Christian Schröder, Stephan Siegel, Johannes-Peter Stasch, Stefan Weigand

Affiliation

¹ BAYER HealthCare AG, Business Group Pharma, Research & Development, D-42096 Wuppertal, Germany. [email protected]

PMID: 16085415
DOI: 10.1016/j.bmcl.2005.06.085

Abstract

A novel class of indole-based endothelin-converting enzyme (ECE) inhibitors was identified by high throughput screening. We report systematic optimization of this compound class by means of classical and solid-phase chemistry. Optimized compounds with a bisarylamide side chain at the 2-position of the indole skeleton exhibit low-nanomolar activity on ECE.

MeSH terms

Aspartic Acid Endopeptidases / antagonists & inhibitors*
Combinatorial Chemistry Techniques
Drug Evaluation, Preclinical / methods
Endothelin-Converting Enzymes
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Humans
Indoles / chemical synthesis*
Indoles / pharmacology
Inhibitory Concentration 50
Metalloendopeptidases / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Indoles
Aspartic Acid Endopeptidases
Metalloendopeptidases
Endothelin-Converting Enzymes