PDBsum entry 2ftd

Hydrolase

PDB id: 2ftd

Contents

Protein chains

215 a.a. *

Ligands

ILI ×2

Waters ×193

* Residue conservation analysis

PDB id:

2ftd

Name:

Hydrolase

Title:

Crystal structure of cathepsin k complexed with 7-methyl-substituted azepan-3-one compound

Structure:

Cathepsin k. Chain: a, b. Engineered: yes

Source:

Macaca mulatta. Rhesus monkey. Organism_taxid: 9544. Strain: osteoclast. Gene: ctsk. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

2.55Å R-factor: 0.237 R-free: 0.284

Authors:

D.S.Yamashita,Z.Baoguang

Key ref:

D.S.Yamashita et al. (2006). Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J Med Chem, 49, 1597-1612. PubMed id: 16509577 DOI: 10.1021/jm050915u

Date:

24-Jan-06 Release date: 30-Jan-07

Protein chains

P61277  (CATK_MACMU) -  Cathepsin K from Macaca mulatta

Seq: 329 a.a.

Struc: 215 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.38 - cathepsin K.
• Reaction: Broad proteolytic activity. With small-molecule substrates and inhibitors, the major determinant of specificity is P2, which is preferably Leu, Met > Phe, and not Arg.

DOI no: 10.1021/jm050915u

J Med Chem 49:1597-1612 (2006)

PubMed id: 16509577

Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors.

D.S.Yamashita, R.W.Marquis, R.Xie, S.D.Nidamarthy, H.J.Oh, J.U.Jeong, K.F.Erhard, K.W.Ward, T.J.Roethke, B.R.Smith, H.Y.Cheng, X.Geng, F.Lin, P.H.Offen, B.Wang, N.Nevins, M.S.Head, R.C.Haltiwanger, A.A.Narducci Sarjeant, L.M.Liable-Sands, B.Zhao, W.W.Smith, C.A.Janson, E.Gao, T.Tomaszek, M.McQueney, I.E.James, C.J.Gress, D.L.Zembryki, M.W.Lark, D.F.Veber.

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.