Ketoheterocycle-based inhibitors of cathepsin K: a novel entry into the synthesis of peptidic ketoheterocycles.
Ketoheterocyclic inhibitors of cathepsin K have been disclosed. SAR of potency enhancing P2-P3 groups coupled with ketoheterocyclic warheads to provide cathepsin K inhibitors have been described. In addition, a novel route to access alpha-ketothiazoles using a key thioamide functionality has been disclosed. The mild method employed allows for the presence of diverse functional groups, such as amide and carbamate functionalities, commonly found in protease inhibitors that have peptidomimetic scaffolds. This new method should provide a quick entry into functionally diverse protease inhibitors.
Department of Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. francis.x.tavares@gsk.com
Francis X
FX
Tavares
David N
DN
Deaton
Aaron B
AB
Miller
Larry R
LR
Miller
Lois L
LL
Wright
D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D011485:Protein Binding; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D011994:Recombinant Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C117627:CTSV protein, human