Beta-substituted cyclohexanecarboxamide cathepsin K inhibitors: modification of the 1,2-disubstituted aromatic core.
Further SAR study around the central 1,2-disubstituted phenyl of the previously disclosed Cat K inhibitor (-)-1 has demonstrated that the solvent exposed P2-P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings. While some potency loss was observed in the 6-membered heteroaromatic series (IC(50)=1 nM for pyridine-linked 4 vs 0.5 nM for phenyl-linked (+/-)-1), several inhibitors showed a significantly decreased shift in the bone resorption functional assay (10-fold for pyridine 4 vs 53-fold for (-)-1). Though this shift was not reduced in the 5-membered heteroaromatic series, potency against Cat K was significantly improved for thiazole 9 (IC(50)=0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
Robichaud
Joël
J
Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland, Que., Canada H9H 3L1. joel_robichaud@merck.com
Bayly
Christopher I
CI
Black
W Cameron
WC
Desmarais
Sylvie
S
Léger
Serge
S
Massé
Frédéric
F
McKay
Daniel J
DJ
Oballa
Renata M
RM
Pâquet
Julie
J
Percival
M David
MD
Truchon
Jean-François
JF
Wesolowski
Gregg
G
Crane
Sheldon N
SN
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship
D000577:Amides; D003510:Cyclohexanes; D015853:Cysteine Proteinase Inhibitors; D006841:Hydrocarbons, Aromatic; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K