Smithkline Beecham Corporation

Renee Louise DesJarlais

Daniel F Veber

Dennis Shinji Yamashita

Timothy Francis Gallagher

Scott Kevin Thompson

Stacie Marie Halbert

Thomas Joseph Carr

Hye-Ja Oh

Jack Hwekwo Yen

William Edward Bondinell

Sherin Salaheldin Abdel-Meguid

Cheryl Ann Janson

Ward Whitlock Smith, Jr

Baoguang Zhao

The present invention provides bis-aminomethyl carbonyl protease inhibitors and pharmaceutically acceptable salts, hydrates and solvates thereof which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

Protease inhibitors

The present invention provides compounds which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease; hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting said bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

A novel cathepsin K crystalline stucture is identified. Also disclosed are methods of identifying inhibitors of this protease and methods of inhibiting cathepsin K using inhibitors with certain structural, physical and spatial characteristics.

Method of inhibiting cathepsin K

The present invention provides compounds which inhibit proteases, including cathepsin K, pharmaceutical compositions of such compounds, and methods for treating diseases of excessive bone loss or cartilage or matrix degradation, including osteoporosis; gingival disease including gingivitis and periodontitis; arthritis, more specifically, osteoarthritis and rheumatoid arthritis; Paget's disease, hypercalcemia of malignancy; and metabolic bone disease, comprising inhibiting and bone loss or excessive cartilage or matrix degradation by administering to a patient in need thereof a compound of the present invention.

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St. Davids, PA, United States of America

Renee Louise DesJarlais