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.
Novartis Institute of Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA. paul.greenspan@mpi.com
Paul D
PD
Greenspan
Kirk L
KL
Clark
Scott D
SD
Cowen
Leslie W
LW
McQuire
Ruben A
RA
Tommasi
David L
DL
Farley
Elizabeth
E
Quadros
David E
DE
Coppa
Zengming
Z
Du
Zheng
Z
Fang
Huanghai
H
Zhou
John
J
Doughty
Karen T
KT
Toscano
Andrew M
AM
Wigg
Siyuan
S
Zhou
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