title: Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
abstract: Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.
authors.affiliation: Merck Research Laboratories, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@merck.com
authors.forename: Zoran
authors.initials: Z
authors.lastname: Rankovic
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Cai
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kerr
authors.forename: Xavier
authors.initials: X
authors.lastname: Fradera
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.forename: Ashvin
authors.initials: A
authors.lastname: Mistry
authors.forename: William
authors.initials: W
authors.lastname: Finlay
authors.forename: George
authors.initials: G
authors.lastname: McGarry
authors.forename: Fiona
authors.initials: F
authors.lastname: Andrews
authors.forename: Wilson
authors.initials: W
authors.lastname: Caulfield
authors.forename: Iain
authors.initials: I
authors.lastname: Cumming
authors.forename: Maureen
authors.initials: M
authors.lastname: Dempster
authors.forename: John
authors.initials: J
authors.lastname: Waller
authors.forename: Wullie
authors.initials: W
authors.lastname: Arbuckle
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.forename: Iain
authors.initials: I
authors.lastname: Martin
authors.forename: Ann
authors.initials: A
authors.lastname: Mitchell
authors.forename: Clive
authors.initials: C
authors.lastname: Long
authors.forename: Mark
authors.initials: M
authors.lastname: Baugh
authors.forename: Paul
authors.initials: P
authors.lastname: Westwood
authors.forename: Emma
authors.initials: E
authors.lastname: Kinghorn
authors.forename: Phil
authors.initials: P
authors.lastname: Jones
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Uitdehaag
authors.forename: Mario
authors.initials: M
authors.lastname: van Zeeland
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Laurent
authors.initials: L
authors.lastname: Saniere
authors.forename: Andre
authors.initials: A
authors.lastname: Fouquet
authors.forename: François
authors.initials: F
authors.lastname: Chevallier
authors.forename: Hortense
authors.initials: H
authors.lastname: Deronzier
authors.forename: Cecile
authors.initials: C
authors.lastname: Dorleans
authors.forename: Eric
authors.initials: E
authors.lastname: Nicolai
mesh_terms: D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D015195:Drug Design; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D007202:Indicators and Reagents; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis* / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012372:ROC Curve; D013329:Structure-Activity Relationship; D016171:Torsades de Pointes / Q000188:drug therapy
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; D009570:Nitriles; D026902:Potassium Channel Blockers; D011743:Pyrimidines; D056657:Cathepsin K