3O0U

Cathepsin K covalently bound to a cyano-pyrimidine inhibitor with improved selectivity over hERG

Summary for 3O0U

• Entry DOI: 10.2210/pdb3o0u/pdb
• Descriptor: Cathepsin K, 3-{2-[(E)-iminomethyl]-6-propylpyrimidin-4-yl}-N,N-dimethyl-5-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: hydrolase, covalent 2-cyano-pyrimidine inhibitor, reversible covalent bond between cys25 and ligand, bone, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Lysosome: P43235
• Total number of polymer chains: 1
• Total formula weight: 23887.85

Authors

Fradera, X.,van Zeeland, M.,Uitdehaag, J.C.M. (deposition date: 2010-07-20, release date: 2011-03-30, Last modification date: 2024-11-27)

Primary citation

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, J.C.,van Zeeland, M.,Potin, D.,Saniere, L.,Fouquet, A.,Chevallier, F.,Deronzier, H.,Dorleans, C.,Nicolai, E.
Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.
Bioorg.Med.Chem.Lett., 20:6237-6241, 2010

PubMed 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.

PubMed: 20843687
DOI: 10.1016/j.bmcl.2010.08.101

Experimental method

X-RAY DIFFRACTION (1.8 Å)