Structure Activity Relationships of 5-, 6-, and 7-Methyl-Substituted Azepan-3-one Cathepsin K Inhibitors

The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substit...

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Published in:	Journal of medicinal chemistry Vol. 49; no. 5; pp. 1597 - 1612
Main Authors:	Yamashita, Dennis S, Marquis, Robert W, Xie, Ren, Nidamarthy, Sirishkumar D, Oh, Hye-Ja, Jeong, Jae U, Erhard, Karl F, Ward, Keith W, Roethke, Theresa J, Smith, Brian R, Cheng, H-Y, Geng, Xiaoliu, Lin, Fan, Offen, Priscilla H, Wang, Bing, Nevins, Neysa, Head, Martha S, Haltiwanger, R. Curtis, Narducci Sarjeant, Amy A, Liable-Sands, Louise M, Zhao, Baoguang, Smith, Ward W, Janson, Cheryl A, Gao, Enoch, Tomaszek, Thaddeus, McQueney, Michael, James, Ian E, Gress, Catherine J, Zembryki, Denise L, Lark, Michael W, Veber, Daniel F
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 09-03-2006
Subjects:	Animals Azepines - chemical synthesis Azepines - chemistry Azepines - pharmacology Biological and medical sciences Biological Availability Blood Proteins - metabolism Bone Density Conservation Agents - chemical synthesis Bone Density Conservation Agents - chemistry Bone Density Conservation Agents - pharmacology Bones, joints and connective tissue. Antiinflammatory agents Cathepsin K Cathepsins - antagonists & inhibitors Cathepsins - chemistry Cell Line Cell Membrane Permeability Crystallography, X-Ray Haplorhini Humans Medical sciences Molecular Conformation Pharmacology. Drug treatments Protein Binding Rats Stereoisomerism Structure-Activity Relationship Sulfones - chemical synthesis Sulfones - chemistry Sulfones - pharmacology Intravenous administration Rat Cysteine endopeptidases Monkey Non peptide compound Clearance Pyridine derivatives Structure activity relation Primates Chemical synthesis Cathepsin K Sulfonamide Enzyme Rodentia Oral administration Enzyme inhibitor Resorption Bioavailability In vitro Peptidases Vertebrata Mammalia Animal Hydrolases Carboxamide Benzofuran derivatives Bone Pharmacokinetics
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Summary:	The syntheses, in vitro characterizations, and rat and monkey in vivo pharmacokinetic profiles of a series of 5-, 6-, and 7-methyl-substituted azepanone-based cathepsin K inhibitors are described. Depending on the particular regiochemical substitution and stereochemical configuration, methyl-substituted azepanones were identified that had widely varied cathepsin K inhibitory potency as well as pharmacokinetic properties compared to the 4S-parent azepanone analogue, 1 (human cathepsin K, K i,app = 0.16 nM, rat oral bioavailability = 42%, rat in vivo clearance = 49.2 mL/min/kg). Of particular note, the 4S-7-cis-methylazepanone analogue, 10, had a K i,app = 0.041 nM vs human cathepsin K and 89% oral bioavailability and an in vivo clearance rate of 19.5 mL/min/kg in the rat. Hypotheses that rationalize some of the observed characteristics of these closely related analogues have been made using X-ray crystallography and conformational analysis. These examples demonstrate the potential for modulation of pharmacological properties of cathepsin inhibitors by substituting the azepanone core. The high potency for inhibition of cathepsin K coupled with the favorable rat and monkey pharmacokinetic characteristics of compound 10, also known as SB-462795 or relacatib, has made it the subject of considerable in vivo evaluation for safety and efficacy as an inhibitor of excessive bone resorption in rat, monkey, and human studies, which will be reported elsewhere.
Bibliography:	istex:FC16672AD431F4665E82A71D84D51E5530A0082A ark:/67375/TPS-9WJTGJL8-D ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm050915u