Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers.
The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 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
Chatterjee
Arnab K
AK
Alper
Phil B
PB
Epple
Robert
R
Williams
Jennifer A
JA
Roberts
Michael J
MJ
Woodmansee
David H
DH
Masick
Brian T
BT
Tumanut
Christine
C
Li
Jun
J
Spraggon
Glen
G
Hornsby
Michael
M
Chang
Jonathan
J
Tuntland
Tove
T
Hollenbeck
Thomas
T
Gordon
Perry
P
Harris
Jennifer L
JL
Karanewsky
Donald S
DS
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004988:Ethers, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D015032:Zinc
D000577:Amides; D004988:Ethers, Cyclic; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S; D015032:Zinc