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PDBsum entry 2ftd
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References listed in PDB file
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Key reference
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Title
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Structure activity relationships of 5-, 6-, And 7-Methyl-Substituted azepan-3-One cathepsin k inhibitors.
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Authors
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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.
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Ref.
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J Med Chem, 2006,
49,
1597-1612.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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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.
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