Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: heterocyclic P3.
A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.
Tully
David C
DC
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, CA 92121, USA. dtully@gnf.org
Liu
Hong
H
Alper
Phil B
PB
Chatterjee
Arnab K
AK
Epple
Robert
R
Roberts
Michael J
MJ
Williams
Jennifer A
JA
Nguyen
KhanhLinh T
KT
Woodmansee
David H
DH
Tumanut
Christine
C
Li
Jun
J
Spraggon
Glen
G
Chang
Jonathan
J
Tuntland
Tove
T
Harris
Jennifer L
JL
Karanewsky
Donald S
DS
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D051381:Rats
D000577:Amides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D002403:Cathepsins; C028217:cathepsin S