Azepanone-based inhibitors of human and rat cathepsin K.
The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K(i) = 0.16 nM) as well as 24, a potent inhibitor of both human (K(i) = 0.0048 nM) and rat (K(i,app) = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.
Marquis
R W
RW
Department of Medicinal Chemistry, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA. robert_w_marquis@sbphrd.com
Ru
Y
Y
LoCastro
S M
SM
Zeng
J
J
Yamashita
D S
DS
Oh
H J
HJ
Erhard
K F
KF
Davis
L D
LD
Tomaszek
T A
TA
Tew
D
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Salyers
K
K
Proksch
J
J
Ward
K
K
Smith
B
B
Levy
M
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Cummings
M D
MD
Haltiwanger
R C
RC
Trescher
G
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Wang
B
B
Hemling
M E
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Quinn
C J
CJ
Cheng
H Y
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Lin
F
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Smith
W W
WW
Janson
C A
CA
Zhao
B
B
McQueney
M S
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D'Alessio
K
K
Lee
C P
CP
Marzulli
A
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Dodds
R A
RA
Blake
S
S
Hwang
S M
SM
James
I E
IE
Gress
C J
CJ
Bradley
B R
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Lark
M W
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Gowen
M
M
Veber
D F
DF
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010010:Osteoclasts / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C425781:5-(2-morpholin-4-ylethoxy)benzofuran-2-carboxylic acid (3-methyl-1-(3-oxo-1-(2-(3-pyridin-2-ylphenyl)acetyl)azepan-4-ylcarbamoyl)butyl)amide; D001381:Azepines; D004791:Enzyme Inhibitors; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat; D007930:Leucine