title: Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.
abstract: The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K(i,app) = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K(i,app) = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville Rd, Collegeville, Pennsylvania 19426, USA. Dennis.S.Yamashita@gsk.com
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Robert W
authors.initials: RW
authors.lastname: Marquis
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Sirishkumar D
authors.initials: SD
authors.lastname: Nidamarthy
authors.forename: Hye-Ja
authors.initials: HJ
authors.lastname: Oh
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jeong
authors.forename: Karl F
authors.initials: KF
authors.lastname: Erhard
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethke
authors.forename: Brian R
authors.initials: BR
authors.lastname: Smith
authors.forename: H-Y
authors.initials: HY
authors.lastname: Cheng
authors.forename: Xiaoliu
authors.initials: X
authors.lastname: Geng
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.forename: Priscilla H
authors.initials: PH
authors.lastname: Offen
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Neysa
authors.initials: N
authors.lastname: Nevins
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Haltiwanger
authors.forename: Amy A
authors.initials: AA
authors.lastname: Narducci Sarjeant
authors.forename: Louise M
authors.initials: LM
authors.lastname: Liable-Sands
authors.forename: Baoguang
authors.initials: B
authors.lastname: Zhao
authors.forename: Ward W
authors.initials: WW
authors.lastname: Smith
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Enoch
authors.initials: E
authors.lastname: Gao
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Tomaszek
authors.forename: Michael
authors.initials: M
authors.lastname: McQueney
authors.forename: Ian E
authors.initials: IE
authors.lastname: James
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Gress
authors.forename: Denise L
authors.initials: DL
authors.lastname: Zembryki
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lark
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D000882:Haplorhini; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001381:Azepines; D001798:Blood Proteins; D050071:Bone Density Conservation Agents; D013450:Sulfones; C509706:relacatib; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat