Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S.
Peptidic, non-covalent inhibitors of lysosomal cysteine protease cathepsin S (1 and 2) were investigated due to low oral bioavailability, leading to an improved series of peptidomimetic inhibitors. Utilizing phenyl succinamides as the P2 residue increased the oral exposure of this lead series of compounds, while retaining selective inhibition of the cathepsin S isoform. Concurrent investigation of the P1 and P2 subsites resulted in the discovery of several potent and selective inhibitors of cathepsin S with good pharmacokinetic properties due to the elimination of saturated aliphatic P2 residues.
Chatterjee
Arnab K
AK
Genomics Institute of the Novartis Research Foundation (GNF), 10675 John J. Hopkins Dr., San Diego, CA 92121, USA.
Liu
Hong
H
Tully
David C
DC
Guo
Jianhua
J
Epple
Robert
R
Russo
Ross
R
Williams
Jennifer
J
Roberts
Michael
M
Tuntland
Tove
T
Chang
Jonathan
J
Gordon
Perry
P
Hollenbeck
Thomas
T
Tumanut
Christine
C
Li
Jun
J
Harris
Jennifer L
JL
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D008297:Male; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013386:Succinates
D000577:Amides; D011480:Protease Inhibitors; D013386:Succinates; D002403:Cathepsins; C028217:cathepsin S; C011116:succinamide