title: 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.
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.
authors.affiliation: Merck Research laboratories, MSD, Lanarkshire ML1 5SH, United Kingdom.
authors.forename: Wullie
authors.initials: W
authors.lastname: Arbuckle
authors.forename: Mark
authors.initials: M
authors.lastname: Baugh
authors.forename: Simone
authors.initials: S
authors.lastname: Belshaw
authors.forename: D Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: John
authors.initials: J
authors.lastname: Bruin
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cameron
authors.forename: Chris
authors.initials: C
authors.lastname: Claxton
authors.forename: Maureen
authors.initials: M
authors.lastname: Dempster
authors.forename: Kathryn
authors.initials: K
authors.lastname: Everett
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: William
authors.initials: W
authors.lastname: Hamilton
authors.forename: Philip S
authors.initials: PS
authors.lastname: Jones
authors.forename: Emma
authors.initials: E
authors.lastname: Kinghorn
authors.forename: Clive
authors.initials: C
authors.lastname: Long
authors.forename: Iain
authors.initials: I
authors.lastname: Martin
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009584:Nitrogen / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011480:Protease Inhibitors; D011725:Pyridines; D002403:Cathepsins; C028217:cathepsin S; D009584:Nitrogen