β-Substituted cyclohexanecarboxamide cathepsin K inhibitors: Modification of the 1,2-disubstituted aromatic core

• Published in: Bioorganic & medicinal chemistry letters 2007-06, Vol.17 (11), p.3146-3151
• Main Authors: Robichaud, Joël, Bayly, Christopher I., Black, W. Cameron, Desmarais, Sylvie, Léger, Serge, Massé, Frédéric, McKay, Daniel J., Oballa, Renata M., Pâquet, Julie, Percival, M. David, Truchon, Jean-François, Wesolowski, Gregg, Crane, Sheldon N.
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Biological and medical sciences; Bone resorption; Bones, joints and connective tissue. Antiinflammatory agents; Cathepsin K; Cathepsins - antagonists & inhibitors; Cyclohexanecarboxamide; Cyclohexanes - chemical synthesis; Cyclohexanes - chemistry; Cyclohexanes - pharmacology; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Humans; Hydrocarbons, Aromatic - chemistry; Inhibitor; Inhibitory Concentration 50; Medical sciences; Modeling; Molecular Structure; Nitrile warhead; Osteoporosis; Pharmacology. Drug treatments; Rabbits; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.03.028

Further 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. 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.