Arylaminoethyl amides as novel non-covalent cathepsin K inhibitors.
A series of N(alpha)-benzyloxycarbonyl- and N(alpha)-acyl-L-leucine(2-phenylaminoethyl)amide derivatives were prepared and evaluated for their inhibitory activity against rabbit and human cysteine proteases cathepsins K, L, and S. These data indicate that N(alpha)-acyl-alpha-amino acid-(arylaminoethyl)amides represent a new class of selective non-covalent inhibitors of cathepsin K. Compounds 4b, 4e, and 4g exhibit high potency toward rabbit and human cathepsin K (IC(50) < 0.006 microM) and are characterized by an excellent selectivity profile vs human cathepsins L and S.
Altmann
Eva
E
Renaud
Johanne
J
Green
Jonathan
J
Farley
David
D
Cutting
Brian
B
Jahnke
Wolfgang
W
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005453:Fluorescence; D006801:Humans; D007700:Kinetics; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K