Arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 2: Optimization of P1 and N-aryl.
A systematic study of anilines led to the discovery of a metabolically robust fluoroindoline replacement for the alkoxy aniline toxicophore in 1. Investigations of the P1 pocket resulted in the discovery of a wide tolerance of functionality leading to the discovery of 11 as a potent and selective inhibitor of cathepsin S.
Alper
Phillip B
PB
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, CA 92121, USA. palper@gnf.org
Liu
Hong
H
Chatterjee
Arnab K
AK
Nguyen
KhanhLinh T
KT
Tully
David C
DC
Tumanut
Christine
C
Li
Jun
J
Harris
Jennifer L
JL
Tuntland
Tove
T
Chang
Jonathan
J
Gordon
Perry
P
Hollenbeck
Thomas
T
Karanewsky
Donald S
DS
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000586:Amination; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; 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; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D000431:Ethanol / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000577:Amides; D001555:Benzene Derivatives; D015853:Cysteine Proteinase Inhibitors; D000431:Ethanol; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C028217:cathepsin S; D056657:Cathepsin K