title: Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers.
abstract: The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, CA 92121, USA. dtully@gnf.org
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Phil B
authors.initials: PB
authors.lastname: Alper
authors.forename: Robert
authors.initials: R
authors.lastname: Epple
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Roberts
authors.forename: David H
authors.initials: DH
authors.lastname: Woodmansee
authors.forename: Brian T
authors.initials: BT
authors.lastname: Masick
authors.forename: Christine
authors.initials: C
authors.lastname: Tumanut
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Michael
authors.initials: M
authors.lastname: Hornsby
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollenbeck
authors.forename: Perry
authors.initials: P
authors.lastname: Gordon
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004988:Ethers, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D015032:Zinc
chemical_list: D000577:Amides; D004988:Ethers, Cyclic; D011480:Protease Inhibitors; D002403:Cathepsins; C028217:cathepsin S; D015032:Zinc