β-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 (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.

Graphical abstractFurther SAR around the central 1,2-disubstituted phenyl of the cathepsin K inhibitor 1 demonstrates that this phenyl P2–P3 linker can be replaced by various 5- or 6-membered heteroaromatic rings.Figure optionsDownload full-size imageDownload as PowerPoint slide