title: Azepanone-based inhibitors of human cathepsin S: optimization of selectivity via the P2 substituent.
abstract: A series of azepanone inhibitors of cathepsin S is described. Selectivity over both cathepsin K and cathepsin L was achieved by varying the P2 substituent. Ultimately, a balanced potency and selectivity profile was achieved in compound 39 possessing a 1-methylcyclohexyl alanine at P2 and nicotinamide as the P' substituent. The cellular potency of selected analogs is also described.
authors: GlaxoSmithKline, King of Prussia, PA 19406, United States. Jeffrey.K.Kerns@gsk.com
authors: Jeffrey K
authors: JK
authors: Kerns
authors: Hong
authors: H
authors: Nie
authors: William
authors: W
authors: Bondinell
authors: Katherine L
authors: KL
authors: Widdowson
authors: Dennis S
authors: DS
authors: Yamashita
authors: Attiq
authors: A
authors: Rahman
authors: Patricia L
authors: PL
authors: Podolin
authors: Donald C
authors: DC
authors: Carpenter
authors: Qi
authors: Q
authors: Jin
authors: Benoit
authors: B
authors: Riflade
authors: Xiaoyang
authors: X
authors: Dong
authors: Neysa
authors: N
authors: Nevins
authors: Paul M
authors: PM
authors: Keller
authors: Laura
authors: L
authors: Mitchell
authors: Thaddeus
authors: T
authors: Tomaszek
mesh_terms: D000409:Alanine / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D011480:Protease Inhibitors; D009536:Niacinamide; D002403:Cathepsins; D056668:Cathepsin L; C028217:cathepsin S; D056657:Cathepsin K; D000409:Alanine