N-arylaminonitriles as bioavailable peptidomimetic inhibitors of cathepsin B.
To improve the pharmacokinetics of a previously reported series of dipeptidyl nitrile cathepsin B inhibitors, the P(2)-P(3) amide group was replaced with an arylamine. Further optimization of this template resulted in highly potent and selective inhibitors with excellent oral availability.
Greenspan
Paul D
PD
Novartis Institute of Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA. paul.greenspan@mpi.com
Clark
Kirk L
KL
Cowen
Scott D
SD
McQuire
Leslie W
LW
Tommasi
Ruben A
RA
Farley
David L
DL
Quadros
Elizabeth
E
Coppa
David E
DE
Du
Zengming
Z
Fang
Zheng
Z
Zhou
Huanghai
H
Doughty
John
J
Toscano
Karen T
KT
Wigg
Andrew M
AM
Zhou
Siyuan
S
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002401:Cathepsin B / Q000037:antagonists & inhibitors*; D004151:Dipeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D014961:X-Ray Diffraction
D004151:Dipeptides; D004791:Enzyme Inhibitors; D002401:Cathepsin B