Cathepsin K is one member of a family of cysteine proteases that employ an active-site cysteine residue to promote peptide bond cleavage. Cathepsin K is highly expressed in the osteoclast cells of bone, which are responsible for bone remodeling during development or following a bone fracture. The strength and resilience of bone is a consequence of its composite structure—formed of a matrix of type I collagen (a structural protein) and the inorganic mineral hydroxyapatite. Osteoclast cells secrete acid to dissolve the inorganic component of bone, and produce cathepsin K to degrade the collagen by hydrolysis of its peptide bonds. In patients with osteoporosis, there is an imbalance of bone resorption and bone formation, leading to a net decrease in bone mass and susceptibility to bone fracture. Inhibition of cathepsin K has thus emerged as a promising new therapeutic strategy to reduce bone density loss in patients with osteoporosis.

A common approach to designing cysteine protease inhibitors is to combine a peptidic (substrate-like) structure with an electrophilic group that forms a covalent bond to the active-site cysteine thiol. The electrophilic group should react with the thiol function to form a stable intermediate that does not undergo further reactions that would regenerate the active protease. Various electrophilic carbonyl groups have been evaluated for this purpose (Figure 7.23). Ketones with a leaving group at the alpha position react to form a stable ketone that cannot undergo further hydrolysis reactions. Other ketone electrophiles lacking a leaving group will react reversibly to form hemi-thioacetals that can revert to starting materials but may be kinetically stable, acting as reversible-covalent inhibitors.

Figure 7.23 Examples of carbonyl and related electrophilic groups employed as cysteine-reactive “warheads” in protease inhibitors. As illustrated at bottom, warhead groups can react irreversibly or reversibly with cysteine proteases.

The electrophilic nitrile function in odanacatib was selected because it forms just such a reversible-covalent bond with the catalytic thiol function of cathepsin K (Figure 7.24). The reversible nature of reaction with thiol was expected to minimize the possibility of immunogenicity arising in response to covalent drug-protein conjugates that might be formed with non-targeted proteins in the body. Minimizing the potential for such side effects is essential when developing a drug intended to treat a chronic condition in a large and generally healthy population.

Figure 7.24 Reaction of odanacatib to form a stable thioimidate function.

Several additional features of the odanacatib structure merit mention. The cyclopropyl ring adjacent to the nitrile function was found to limit the extent of amide bond hydrolysis by serum proteases, leading to more sustained drug exposure in the body. This same amide bond forms important hydrogen bonding interactions in the cathepsin K active site that serve to position the nitrile group in proximity to the reactive thiol function. The fluorine atom in the leucine-like side chain of odanacatib was introduced to block the oxidative metabolism of the isopropyl group. In odanacatib analogs lacking the fluorine atom, metabolism resulted in greatly reduced concentrations of circulating drug. Finally, the trifluoromethyl group reduces the basicity of the amine function, allowing the N–H bond to donate a hydrogen bond to the backbone carbonyl of Gly66 in the cathepsin K active site.

Cysteine proteases have long been recognized as attractive drug targets for cancer, inflammation, and neurodegenerative diseases. However, developing safe and effective drugs that inhibit cysteine proteases has been extremely challenging. Should odanacatib ultimately win regulatory approval, it would represent a first-in-class treatment of osteoporosis and a rare example of a covalent (albeit reversible) drug developed for a chronic indication.

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