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A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis

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Piperidine-based renin inhibitors: upper chain optimization.

Olivier Corminboeuf¹, Olivier Bezençon, Luboš Remeň

¹Drug Discovery Chemistry & Biochemistry, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.

Bioorganic & Medicinal Chemistry Letters

|September 17, 2010

Summary

This summary is machine-generated.

Researchers optimized novel piperidine-based renin inhibitors, leading to the discovery of compound 11 (ACT-178882, MK-1597). This potent renin inhibitor shows promise for further therapeutic development.

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Area of Science:

Medicinal Chemistry
Pharmacology
Drug Discovery

Background:

Renin inhibitors are crucial for managing hypertension.
Previous research identified 3,4-disubstituted piperidine scaffolds as promising for renin inhibition.
Optimization of lead compounds is essential for developing effective therapeutics.

Purpose of the Study:

To optimize the 4-position of novel piperidine-based renin inhibitors.
To synthesize and characterize new chemical entities.
To identify a renin inhibitor with a profile suitable for clinical development.

Main Methods:

Systematic chemical modification of the piperidine scaffold at the 4-position.
Synthesis of a library of novel compounds.
In vitro and in vivo characterization of biological activity and pharmacokinetic properties.

Main Results:

Successful optimization of the 4-position led to enhanced renin inhibitory activity.
Compound 11 (ACT-178882, MK-1597) emerged as a potent and selective renin inhibitor.
Compound 11 demonstrated favorable properties for further preclinical and clinical evaluation.

Conclusions:

The 4-position of the piperidine scaffold is a critical determinant of renin inhibitory potency.
Compound 11 represents a significant advancement in the development of novel renin inhibitors.
Further development of compound 11 is warranted for the treatment of renin-dependent diseases.