Design and synthesis of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 1.
A series of Nalpha-acyl-alpha-amino acid-(arylaminoethyl)amides were found to be potent and noncovalent cathepsin S inhibitors. Compound 20 possessed high cathepsin S affinity (Ki=3.3 nM) and showed excellent selectivity over cathepsin K, L, F, and V. Molecular modeling, design, synthesis, and in vitro activity are described.
Liu
Hong
H
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, CA 92121, USA. hliu@gnf.org
Tully
David C
DC
Epple
Robert
R
Bursulaya
Badry
B
Li
Jun
J
Harris
Jennifer L
JL
Williams
Jennifer A
JA
Russo
Ross
R
Tumanut
Christine
C
Roberts
Michael J
MJ
Alper
Phil B
PB
He
Yun
Y
Karanewsky
Donald S
DS
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000586:Amination; D001665:Binding Sites; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D000431:Ethanol / Q000737:chemistry*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000577:Amides; D011480:Protease Inhibitors; D000431:Ethanol; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C028217:cathepsin S; D056657:Cathepsin K