Bioorganic and Medicinal Chemistry Letters p. 3146 - 3151 (2007)
Update date:2022-07-30
Topics:
Robichaud, Joel
Bayly, Christopher I.
Black, W. Cameron
Desmarais, Sylvie
Leger, Serge
Masse, Frederic
McKay, Daniel J.
Oballa, Renata M.
Paquet, Julie
Percival, M. David
Truchon, Jean-Francois
Wesolowski, Gregg
Crane, Sheldon N.
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 (IC50 = 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 (IC50 = 0.2 nM) as was the pharmacokinetic profile of N-methyl pyrazole 10 over our lead compound (-)-1.
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