title: Potent and selective cathepsin K inhibitors.
abstract: A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone.
authors.affiliation: Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, Shinagawa-ku, Tokyo 140-8710, Japan. sinozu@sankyo.co.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shinozuka
authors.forename: Kousei
authors.initials: K
authors.lastname: Shimada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsui
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamane
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Motohiko
authors.initials: M
authors.lastname: Taki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takeda
authors.forename: Eri
authors.initials: E
authors.lastname: Otsuka
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamato
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohhata
authors.forename: Satoru
authors.initials: S
authors.lastname: Naito
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003546:Cysteine Endopeptidases; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D008968:Molecular Conformation; D010052:Ovariectomy; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat; C028217:cathepsin S; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat