Cyclic ketone inhibitors of the cysteine protease cathepsin K.
Cathepsin K (EC 3.4.22.38), a cysteine protease of the papain superfamily, is predominantly expressed in osteoclasts and has been postulated as a target for the treatment of osteoporosis. Crystallographic and structure--activity studies on a series of acyclic ketone-based inhibitors of cathepsin K have led to the design and identification of two series of cyclic ketone inhibitors. The mode of binding for four of these cyclic and acyclic inhibitors to cathepsin K is discussed and compared. All of the structures are consistent with addition of the active site thiol to the ketone of the inhibitors with the formation of a hemithioketal. Cocrystallization of the C-3 diastereomeric 3-amidotetrahydrofuran-4-one analogue 16 with cathepsin K showed the inhibitor to occupy the unprimed side of the active site with the 3S diastereomer preferred. This C-3 stereochemical preference is in contrast to the X-ray cocrystal structures of the 3-amidopyrrolidin-4-one inhibitors 29 and 33 which show these inhibitors to prefer binding of the 3R diastereomer. The 3-amidopyrrolidin-4-one inhibitors were bound in the active site of the enzyme in two alternate directions. Epimerization issues associated with the labile alpha-amino ketone diastereomeric center contained within these inhibitor classes has proven to limit their utility despite promising pharmacokinetics displayed in both series of compounds.
Marquis
R W
RW
Department of Medicinal Chemistry, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. Robert_W_Marquis@sbphrd.com
Ru
Y
Y
Zeng
J
J
Trout
R E
RE
LoCastro
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Gribble
A D
AD
Witherington
J
J
Fenwick
A E
AE
Garnier
B
B
Tomaszek
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T
Tew
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D
Hemling
M E
ME
Quinn
C J
CJ
Smith
W W
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Zhao
B
B
McQueney
M S
MS
Janson
C A
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D'Alessio
K
K
Veber
D F
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D000818:Animals; D001665:Binding Sites; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002853:Chromatography, Liquid; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005663:Furans; D007659:Ketones; D010880:Piperidines; D011714:Pyrans; D011760:Pyrrolidinones; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat