Inhibitors of cathepsin K: a patent review (2004 – 2010)

Abstract

Between 2004 and 2010, more than 50 patent applications have appeared, underlining the continued interest in small molecule cathepsin K inhibition for therapeutic intervention. Most compounds claimed are peptide-derived inhibitors displaying a reversible binding nitrile or ketone warhead. The success of these compounds in the clinic will be determined by the selectivity that can be achieved against other off-target cathepsin. In this respect, eliminating lysosomotropic characteristics may prove to be crucial in the design of selective cathepsin K inhibitors. During the review period, ONO-5334 and odanacatib have progressed to Phase II and Phase III clinical trials, respectively. The results of these studies are eagerly awaited and may determine the future of these agents as disease-modifying therapeutics.

Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors

“…For the almost two past decades, pharmaceutical industry has been focusing on the development of reversible covalent Cat K inhibitors for osteoporosis treatment based on nitrile or carbonyl warheads. 15, 16 The most advanced drug candidates such as ONO-5334 and Odanacatib are currently in clinical trials with Odanacatib successfully concluding the first phase III in post-menopausal women with osteoporosis ( Figure 1a). [17][18][19][20][21][22][23][24][25] In contrast, the phase II clinical trials with N- [4-(4-propyl-piperazino)benzoyl]-homocycloleucyl-glycinonitrile Balicatib were discontinued due to unexpected off-target effects.…”

“…The hydrophobic S2 site with main chain amide and carbonyl groups of Gly66 as hydrogen donors and acceptors of the main chain P2 residue and hydrophobic moiety of the S2 site spanned between Tyr67, Ala134, and Leu209, and the S3 area , which is relatively shallow and solvent-exposed ( Figure 1b). 16,28,29 homocycloleucyl-glycinonitriles within the Cat K active site indicated by S1−S3 subsites.…”

An oral cathepsin K inhibitor ONO-5334 inhibits N- terminal and C- terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women

“…ACCEPTED MANUSCRIPT 12 unclear, but the results might be related to the low correlations with other bone markers.…”

Pharmacological diversity among drugs that inhibit bone resorption

“…Cathepsin K therefore became an attractive therapeutic target in osteoporosis, and also potentially in other conditions, such as osteoarthritis and bone cancers. This led to flurry of research activity, particularly in the 1990s, and medicinal chemists designed and synthesized many inhibitors with varying degrees of selectivity [80] and many patents have been issued [81]. However many hurdles have been encountered during the discovery and development of cathepsin K inhibitors as drugs [82].…”