Substrate-derived triazolo- and azapeptides as inhibitors of cathepsins K and S (original) (raw)

N-formylpyrazolines and N-benzoylpyrazolines as potential inhibitors cathepsin L

AIMS molecular science, 2016

Cathepsins, intracellular proteases, are known to be involved in a number of physiological processes ranging from degradation of extracellular proteins, prohormone processing, progressions of atherosclerosis, etc. High levels of cathepsins have been indicated in various pathological conditions like arthritis, cancer and other tissue degenerative disorders. One of the reasons attributed to these high levels is decrease in inhibitor concentration. Therefore, the work on the identification of small molecular weight compounds as inhibitors of cysteine proteases is of great therapeutic significance. Exploring this work in the same direction, we here present the synthesis of substituted N-formylpyrazolines and N-benzoylpyrazolines and study these as inhibitors to cysteine proteases. After a preliminary screening of the compounds as inhibitors to cysteine proteases in general, studies were carried out to study their inhibitory effects on cathepsin B and cathepsin H. SAR studies show that N-formylpyrazolines were better inhibitors than N-benzoylpyrazolines. The most potent inhibitors among the two series were nitro substituted compounds 1i and 2i with K i values of 1.1A^10Aˋ9Mand19.5A^10Aˋ8MforcathepsinBandKivaluesof1.1 Â 10 À9 M and 19.5 Â 10 À8 M for cathepsin B and K i values of 1.1A^10Aˋ9Mand19.5A^10Aˋ8MforcathepsinBandKivaluesof5.19 Â 10 À8 M and 9.8 Â 10 À7 M for cathepsin H, respectively. Docking experiments showing interaction between N-formylpyrazolines and N-benzoylpyrazolines with enzyme active sites structures also provided useful insights.

Diazinones as P2 replacements for pyrazole-based cathepsin S inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

A pyridazin-4-one fragment 4 (hCatS IC 50 = 170 lM) discovered through Tethering was modeled into cathepsin S and predicted to overlap in S2 with the tetrahydropyridinepyrazole core of a previously disclosed series of CatS inhibitors. This fragment served as a template to design pyridazin-3-one 12 (hCatS IC 50 = 430 nM), which also incorporates P3 and P5 binding elements. A crystal structure of 12 bound to Cys25Ser CatS led to the synthesis of the potent diazinone isomers 22 (hCatS IC 50 = 60 nM) and 27 (hCatS IC 50 = 40 nM).

Dioxo-triazines as a novel series of cathepsin K inhibitors

Bioorganic & Medicinal Chemistry Letters, 2010

A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC 50 values of 17 nM against catK and >10,000 nM in catL, catB and catS assays.

In Search of Selective Inhibitors of Cysteine Protease, Cathepsin K

International Journal of Peptide Research and Therapeutics, 2005

Two potential azapeptide inhibitors of cathepsin K were designed and synthesized. To analyze in detail interactions between these azainhibitors and the investigated cysteine protease, molecular dynamics simulations were performed. For the obtained compounds the equilibrium constants for dissociation of inhibitor -enzyme complex, K i , were determined. The examined azapeptides proved to be not as potent inhibitors of cathepsin K as they were expected to be according to the results of simulations. However, these calculations provide valuable information about probable structures of this type of peptidomimetics in the catalytic pocket of cathepsin K, which could be useful in designing of more selective inhibitors of this cysteine protease.

A Review on Azapeptides: The Promising Peptidomimetics

Asian Journal of Chemistry

Peptidomimetics, the mimics of natural peptides are considered as promising therapeutics with potential applications in modern medicine. Among the various structural variants of peptidomimetics that have been designed and synthesized, the azapeptides serve as the interesting peptide backbone modifications owing to their diversified biological and pharmacokinetic properties. The aim of this review is to highlight the significance of azapeptide in enhancement of stability and bioavailability, represent the various scaffolds of azapeptides as peptidomimetics, notify their significance as cysteine and serine protease inhibitors, provide an insight on the various biologically significant azapeptides and emphasize the main features on the conventional to modified synthetic strategies of azapeptides.

Design of potent and selective human cathepsin K inhibitors that span the active site

Proceedings of the National Academy of Sciences, 1997

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors

Bioorganic & Medicinal Chemistry Letters, 2004

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays. #