1.
Bioorg Med Chem Lett
; 19(6): 1658-61, 2009 Mar 15.
Article
in English
| MEDLINE
| ID: mdl-19231183
ABSTRACT
A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Nitriles/chemical synthesis , Cathepsin K , Cathepsins/chemistry , Chemistry, Pharmaceutical/methods , Cysteine Proteinase Inhibitors/pharmacology , Drug Design , Humans , Lysosomes/enzymology , Models, Chemical , Molecular Structure , Osteoarthritis/drug therapy , Osteoclasts , Osteoporosis/drug therapy , Pyrimidines/chemistry , Structure-Activity Relationship , Technology, Pharmaceutical/methods
2.
Bioorg Med Chem Lett
; 17(2): 370-5, 2007 Jan 15.
Article
in English
| MEDLINE
| ID: mdl-17095213
ABSTRACT
Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.
