Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
Basic Information
ID: ALA1268809
Journal: Bioorg Med Chem Lett
Title: Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
Authors: Rankovic Z, Cai J, Kerr J, Fradera X, Robinson J, Mistry A, Finlay W, McGarry G, Andrews F, Caulfield W, Cumming I, Dempster M, Waller J, Arbuckle W, Anderson M, Martin I, Mitchell A, Long C, Baugh M, Westwood P, Kinghorn E, Jones P, Uitdehaag JC, van Zeeland M, Potin D, Saniere L, Fouquet A, Chevallier F, Deronzier H, Dorleans C, Nicolai E.
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.
CiteXplore: 20843687
DOI: 10.1016/j.bmcl.2010.08.101
Patent ID: ┄