title: Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K.
abstract: We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
authors.affiliation: Celera Genomics, Inc., 180 Kimball Way, South San Francisco, California 94080, USA. jim.palmer@celera.com
authors.forename: James T
authors.initials: JT
authors.lastname: Palmer
authors.forename: Clifford
authors.initials: C
authors.lastname: Bryant
authors.forename: Dan-Xiong
authors.initials: DX
authors.lastname: Wang
authors.forename: Dana E
authors.initials: DE
authors.lastname: Davis
authors.forename: Eduardo L
authors.initials: EL
authors.lastname: Setti
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rydzewski
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Zong-Qiang
authors.initials: ZQ
authors.lastname: Tian
authors.forename: Leland C
authors.initials: LC
authors.lastname: Burrill
authors.forename: Rohan V
authors.initials: RV
authors.lastname: Mendonca
authors.forename: Eric
authors.initials: E
authors.lastname: Springman
authors.forename: John
authors.initials: J
authors.lastname: McCarter
authors.forename: Tobee
authors.initials: T
authors.lastname: Chung
authors.forename: Harry
authors.initials: H
authors.lastname: Cheung
authors.forename: James W
authors.initials: JW
authors.lastname: Janc
authors.forename: Mary
authors.initials: M
authors.lastname: McGrath
authors.forename: John R
authors.initials: JR
authors.lastname: Somoza
authors.forename: Philip
authors.initials: P
authors.lastname: Enriquez
authors.forename: Z Walter
authors.initials: ZW
authors.lastname: Yu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strickley
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Venuti
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.forename: Sevgi B
authors.initials: SB
authors.lastname: Rodan
authors.forename: Colena
authors.initials: C
authors.lastname: Johnson
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kimmel
authors.forename: Gideon
authors.initials: G
authors.lastname: Rodan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D015415:Biomarkers / Q000652:urine; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000652:urine; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002417:Cattle; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D015415:Biomarkers; D050071:Bone Density Conservation Agents; C507712:CRA 013783; D009570:Nitriles; D013844:Thiazoles; D003094:Collagen; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat