Stacey T. Long scite author profile

et al. 2003

J. Med. Chem.

Journal of Pharmaceutical Sciences

Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis

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Dehydration, hydration behavior, and structural analysis of fenoprofen calcium**This work is presented in memory of one of the authors, Jia Xu.

Zhu

Varlashkin

et al. 2001

P2–P3 conformationally constrained ketoamide-based inhibitors of cathepsin K

Boncek

Catalano

et al. 2005

Journal of Pharmaceutical Sciences

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: Crystal structures and multinuclear solid-state NMR

Vogt

Katrincic

Long

et al. 2008

Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors?

Adkison

et al. 2006

A structural screening approach to ketoamide-based inhibitors of cathepsin K

Catalano

et al. 2005

Potent and selective P2–P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1′, P1, and/or P3 substitutions

Catalano

et al. 2004