Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
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.
Rankovic
Zoran
Z
Merck Research Laboratories, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@merck.com
Cai
Jiaqiang
J
Kerr
Jennifer
J
Fradera
Xavier
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Robinson
John
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Mistry
Ashvin
A
Finlay
William
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McGarry
George
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Andrews
Fiona
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Caulfield
Wilson
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Cumming
Iain
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Dempster
Maureen
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Waller
John
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Arbuckle
Wullie
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Anderson
Mark
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Martin
Iain
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Mitchell
Ann
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Long
Clive
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Baugh
Mark
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Westwood
Paul
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Kinghorn
Emma
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Jones
Phil
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Uitdehaag
Joost C M
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van Zeeland
Mario
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Potin
Dominique
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Saniere
Laurent
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Fouquet
Andre
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Chevallier
François
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Deronzier
Hortense
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Dorleans
Cecile
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Nicolai
Eric
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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
D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; D009570:Nitriles; D026902:Potassium Channel Blockers; D011743:Pyrimidines; D056657:Cathepsin K