Arylamine based cathepsin K inhibitors: Investigating P3 heterocyclic substituents

• Published in: Bioorganic & medicinal chemistry 2006-10, Vol.14 (20), p.6807-6819
• Main Authors: Shinozuka, Tsuyoshi, Shimada, Kousei, Matsui, Satoshi, Yamane, Takahiro, Ama, Mayumi, Fukuda, Takeshi, Taki, Motohiko, Takeda, Yuko, Otsuka, Eri, Yamato, Michiko, Naito, Satoru
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cathepsin B - antagonists & inhibitors; Cathepsin K; Cathepsin L; Cathepsins - antagonists & inhibitors; Cysteine Endopeptidases; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; Heterocyclic substituent; Humans; Inhibitor; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Recombinant Proteins - antagonists & inhibitors; SAR study; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.06.031

The synthesis, SARs, selectivity over other human cathepsins, and pharmacokinetics of heterocyclic substituted cathepsin K inhibitors are reported. A modification of novel cathepsin K inhibitors I was carried out. The structural design was aimed at reducing the lipophilic character of compounds I for obtaining better pharmacokinetic profiles. This modification afforded several less lipophilic compounds with good inhibitory activities and pharmacokinetic profiles, although the enzyme selectivity over cathepsin S was left at issue.