title: Synthesis and SAR of succinamide peptidomimetic inhibitors of cathepsin S.
abstract: 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.
authors: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John J. Hopkins Dr., San Diego, CA 92121, USA.
authors: Arnab K
authors: AK
authors: Chatterjee
authors: Hong
authors: H
authors: Liu
authors: David C
authors: DC
authors: Tully
authors: Jianhua
authors: J
authors: Guo
authors: Robert
authors: R
authors: Epple
authors: Ross
authors: R
authors: Russo
authors: Jennifer
authors: J
authors: Williams
authors: Michael
authors: M
authors: Roberts
authors: Tove
authors: T
authors: Tuntland
authors: Jonathan
authors: J
authors: Chang
authors: Perry
authors: P
authors: Gordon
authors: Thomas
authors: T
authors: Hollenbeck
authors: Christine
authors: C
authors: Tumanut
authors: Jun
authors: J
authors: Li
authors: Jennifer L
authors: JL
authors: Harris
mesh_terms: 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
chemical_list: D000577:Amides; D011480:Protease Inhibitors; D013386:Succinates; D002403:Cathepsins; C028217:cathepsin S; C011116:succinamide