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Page 10 of 17 Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09

In addition to AZD7986, two other cathepsin C inhibitors have entered clinical trials. Compound
GSK2793660 [Table 1] was developed by GlaxoSmithKline (UK) and is a dipeptide-based irreversible
inhibitor with an α,β-unsaturated amide-reactive group. Unfortunately, clinical trials were discontinued
after several volunteers in a phase 1 study showed symptoms of epidermal desquamation of the palms and
soles after repeated administration of the inhibitor, which bore some resemblance to PLS patients. In
[111]
addition, no significant reduction in NSP activity was observed . The third compound, BI1291583
(undisclosed structure), developed by Boehringer Ingelheim (Germany), has just started a phase 2 trial for
[112]
the treatment of bronchiectasis (NCT05238675) after successfully completing phase 1 and is expected to
be completed in Q1 of 2024.

Based on the successes and failures of these inhibitors, novel non-peptidic, non-covalent inhibitors of
[114]
cathepsin C are emerging in recent years . Chen et al. synthesized and characterized a series of inhibitors
based on a pyridine scaffold. The best compound had a reported IC value of 57.4 ± 0.7 nM and was
50
selective for cathepsin C in vitro [Table 1]. Its administration also reduced NSP activation in rat bone
[115]
marrow and showed anti-inflammatory activity in a rat model of COPD . The compound was recently
[115]
further optimized to improve its pharmacokinetic properties . Further research will shed light on the
[116]
efficacy and safety of these compounds.
In addition, a substantial number of cathepsin C inhibitors have been reported that have provided only in
vitro data and no in vivo follow-up studies to date. Using a structure-based approach, Radzey et al. used E-
64c hydrazide as a lead structure for the development of irreversible cathepsin C inhibitors . The best
[117]
resulting inhibitor, (2S,3S)-3-(2-butylhydrazine carbonyl)-N-((S)-1-(isopentylamino)-4-methyl-1-
oxopentan-2-yl)oxirane-2-carboxamide [Table 1], exhibits significantly improved potency (k = (5.6 ±
inact
4
0.17) × 10 M s ) compared to E-64c-hydrazide (k = 140 ± 5 M s ). It also reacts more rapidly with
-1
-1
-1
-1
inact
cathepsin C than with cathepsin L, which is the opposite of E-64c and its hydrazide, which have a strong
[117]
preference for cathepsin L . The authors therefore proposed this compound as a starting point for the
development of optimized inhibitors that bind to the S1'-S2' sites of cathepsin C .
[117]
Azapeptides, i.e., peptide analogs in which one or more amino acids have been replaced by a semicarbazide
group, have been reported as inhibitors of hepatitis C virus NS3 peptidase , human rhinovirus 3C
[118]
peptidase , and several papain-like cysteine peptidases . Azapeptides with weak leaving groups cannot
[119]
[120]
acylate the enzyme and therefore show competitive inhibition, whereas azapeptides with reactive leaving
groups form carbamoyl-enzyme complexes that are more stable than normal acyl enzymes. For cathepsin C,
one of the best inhibitors from this class was 1-(2S-2-aminobutanoyl)-4-{2S-N-[2S-3-(m-fluoro-
phenyl)propan-2-yl-amide]-4-phenylbutan-2-yl-amide}semi- carbazide [Table 1] with an IC value of 31 ±
50
3 nM and a K value of 45 ± 2 nM. The compound acted as a reversible, competitive inhibitor and was
i
selective for cathepsin C. It was not cytotoxic to HepG2 cells and showed about 50% inhibition of
intracellular cathepsin C activity in this cell line .
[121]
Drag et al. described a series of phosphonate dipeptide analogs as non-covalent inhibitors of cathepsin C
[122] . The most potent compounds, diethyl 2-(L-phenylalanyl) amino-1-hydroxymethane phosphonate and
monomethyl 2-(L-phenylalanyl) amino-1-hydroxyethane phosphonate [Table 1], inhibited cathepsin C with
K values in the nanomolar range (23 ± 12 nM and 51 ± 16 nM, respectively). Unfortunately, these
i
compounds exhibited low selectivity for cathepsin C, as they have also been shown to be potent inhibitors of
other cysteine peptidases such as papain, cathepsin B, and cathepsin K . Nevertheless, the phosphonate
[122]
dipeptide analogs identified in this study could serve as lead compounds for the development of more
specific inhibitors of cathepsin C and/or other cysteine cathepsins. Similarly, a group of tripeptide