title: Azepanone-based inhibitors of human and rat cathepsin K.
abstract: The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.
authors: Department of Medicinal Chemistry, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. robert_w_marquis@sbphrd.com
authors: R W
authors: RW
authors: Marquis
authors: Y
authors: Y
authors: Ru
authors: S M
authors: SM
authors: LoCastro
authors: J
authors: J
authors: Zeng
authors: D S
authors: DS
authors: Yamashita
authors: H J
authors: HJ
authors: Oh
authors: K F
authors: KF
authors: Erhard
authors: L D
authors: LD
authors: Davis
authors: T A
authors: TA
authors: Tomaszek
authors: D
authors: D
authors: Tew
authors: K
authors: K
authors: Salyers
authors: J
authors: J
authors: Proksch
authors: K
authors: K
authors: Ward
authors: B
authors: B
authors: Smith
authors: M
authors: M
authors: Levy
authors: M D
authors: MD
authors: Cummings
authors: R C
authors: RC
authors: Haltiwanger
authors: G
authors: G
authors: Trescher
authors: B
authors: B
authors: Wang
authors: M E
authors: ME
authors: Hemling
authors: C J
authors: CJ
authors: Quinn
authors: H Y
authors: HY
authors: Cheng
authors: F
authors: F
authors: Lin
authors: W W
authors: WW
authors: Smith
authors: C A
authors: CA
authors: Janson
authors: B
authors: B
authors: Zhao
authors: M S
authors: MS
authors: McQueney
authors: K
authors: K
authors: D'Alessio
authors: C P
authors: CP
authors: Lee
authors: A
authors: A
authors: Marzulli
authors: R A
authors: RA
authors: Dodds
authors: S
authors: S
authors: Blake
authors: S M
authors: SM
authors: Hwang
authors: I E
authors: IE
authors: James
authors: C J
authors: CJ
authors: Gress
authors: B R
authors: BR
authors: Bradley
authors: M W
authors: MW
authors: Lark
authors: M
authors: M
authors: Gowen
authors: D F
authors: DF
authors: Veber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010010:Osteoclasts / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C425781:5-(2-morpholin-4-ylethoxy)benzofuran-2-carboxylic acid (3-methyl-1-(3-oxo-1-(2-(3-pyridin-2-ylphenyl)acetyl)azepan-4-ylcarbamoyl)butyl)amide; D001381:Azepines; D004791:Enzyme Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat; D007930:Leucine