Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors

Jiaqiang Cai; John Robinson; Simone Belshaw; Kathryn Everett; Xavier Fradera; Mario van Zeeland; Leon van Berkom; Peter van Rijnsbergen; Lucy Popplestone; Mark Baugh; Maureen Dempster; John Bruin; William Hamilton; Emma Kinghorn; Paul Westwood; Jennifer Kerr; Zoran Rankovic; Wullie Arbuckle; D Jonathan Bennett; Philip S Jones; Clive Long; Iain Martin; Joost C M Uitdehaag; Tommi Meulemans

doi:10.1016/j.bmcl.2010.10.012

Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors

Bioorg Med Chem Lett. 2010 Dec 1;20(23):6890-4. doi: 10.1016/j.bmcl.2010.10.012. Epub 2010 Oct 26.

Affiliation

¹ Merck Research Laboratories, MSD, Newhouse, Lanarkshire, United Kingdom. jiaqiang.cai@merck.com

PMID: 21030256
DOI: 10.1016/j.bmcl.2010.10.012

Abstract

The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.

MeSH terms

Amides / chemical synthesis
Amides / pharmacology
Aniline Compounds / chemical synthesis*
Aniline Compounds / pharmacology
Animals
Cathepsins / antagonists & inhibitors*
Cysteine Proteinase Inhibitors / chemical synthesis*
Cysteine Proteinase Inhibitors / pharmacology
Fluorine
Humans
Ketones
Structure-Activity Relationship

Substances

Amides
Aniline Compounds
Cysteine Proteinase Inhibitors
Ketones
Fluorine
Cathepsins
cathepsin S