1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka

Wullie Arbuckle; Mark Baugh; Simone Belshaw; D Jonathan Bennett; John Bruin; Jiaqiang Cai; Kenneth S Cameron; Chris Claxton; Maureen Dempster; Kathryn Everett; Xavier Fradera; William Hamilton; Philip S Jones; Emma Kinghorn; Clive Long; Iain Martin; John Robinson; Paul Westwood

doi:10.1016/j.bmcl.2010.12.065

1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka

Bioorg Med Chem Lett. 2011 Feb 1;21(3):932-5. doi: 10.1016/j.bmcl.2010.12.065. Epub 2010 Dec 19.

Authors

Wullie Arbuckle¹, Mark Baugh, Simone Belshaw, D Jonathan Bennett, John Bruin, Jiaqiang Cai, Kenneth S Cameron, Chris Claxton, Maureen Dempster, Kathryn Everett, Xavier Fradera, William Hamilton, Philip S Jones, Emma Kinghorn, Clive Long, Iain Martin, John Robinson, Paul Westwood

Affiliation

¹ Merck Research laboratories, MSD, Lanarkshire ML1 5SH, United Kingdom.

PMID: 21227690
DOI: 10.1016/j.bmcl.2010.12.065

Abstract

Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.

MeSH terms

Animals
Cathepsins / antagonists & inhibitors*
Cathepsins / metabolism
Mice
Nitrogen / chemistry*
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacokinetics
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacokinetics
Rats
Rats, Sprague-Dawley

Substances

Protease Inhibitors
Pyridines
Cathepsins
cathepsin S
Nitrogen