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Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
Rankovic, Zoran; Cai, Jiaqiang; Kerr, Jennifer; Fradera, Xavier; Robinson, John; Mistry, Ashvin; Finlay, William; McGarry, George; Andrews, Fiona; Caulfield, Wilson; Cumming, Iain; Dempster, Maureen; Waller, John; Arbuckle, Wullie; Anderson, Mark; Martin, Iain; Mitchell, Ann; Long, Clive; Baugh, Mark; Westwood, Paul; Kinghorn, Emma; Jones, Phil; Uitdehaag, Joost C M; van Zeeland, Mario; Potin, Dominique; Saniere, Laurent; Fouquet, Andre; Chevallier, François; Deronzier, Hortense; Dorleans, Cecile; Nicolai, Eric.
Affiliation
  • Rankovic Z; Merck Research Laboratories, MSD, Newhouse, Lanarkshire, ML1 5SH Scotland, United Kingdom. zoran.rankovic@merck.com
Bioorg Med Chem Lett ; 20(21): 6237-41, 2010 Nov 01.
Article in En | MEDLINE | ID: mdl-20843687
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Potassium Channel Blockers / Ether-A-Go-Go Potassium Channels / Cathepsin K / Nitriles Type of study: Prognostic_studies Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2010 Document type: Article Affiliation country: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidines / Potassium Channel Blockers / Ether-A-Go-Go Potassium Channels / Cathepsin K / Nitriles Type of study: Prognostic_studies Language: En Journal: Bioorg Med Chem Lett Journal subject: BIOQUIMICA / QUIMICA Year: 2010 Document type: Article Affiliation country: Reino Unido