362530-16-3Relevant academic research and scientific papers
Design, synthesis and biological evaluation of inhibitors of cathepsin K on dedifferentiated chondrocytes
Yuan, Xiao-Yu,Ren, Zhongyuan,Wu, Yuqing,Bougault, Carole,Brizuela, Leyre,Magne, David,Buchet, René,Mebarek, Saida
, p. 1034 - 1042 (2019)
Selective proteinase inhibitors have demonstrated utility in the investigation of cartilage degeneration mechanisms and may have clinical use in the management of osteoarthritis. The cysteine protease cathepsin K (CatK) is an attractive target for arthritis therapy. Here we report the synthesis of two cathepsin K inhibitors (CKIs): racemic azanitrile derivatives CKI-E and CKI-F, which have better inhibition properties on CatK than the commercial inhibitor odanacatib (ODN). Their IC50 values and inhibition constants (Ki) have been determined in vitro. Inhibitors demonstrate differential selectivity for CatK over cathepsin B, L and S in vitro, with Ki amounting to 1.14 and 7.21 nM respectively. We analyzed the effect of these racemic inhibitors on viability in different cell types. The human osteoblast-like cell line MG63, MOVAS cells (a murine vascular smooth muscle cell line) or murine primary chondrocytes, were treated either with CKI-E or with CKI-F, which were not toxic at doses of up to 5 μM. Primary chondrocytes subjected to several passages were used as a model of phenotypic loss of articular chondrocytes, occurring in osteoarthritic cartilage. The efficiency of CKIs regarding CatK inhibition and their specificity over other proteases were validated in primary chondrocytes subjected to several passages. Racemic CKI-E and CKI-F at 0.1 and 1 μM significantly inhibited CatK activity in dedifferentiated chondrocytes, even better than the commercial CatK inhibitor ODN. The enzymatic activity of other proteases such as matrix metalloproteinases or aggrecanases were not affected. Taken together, these findings support the possibility to design CatK inhibitors for preventing cartilage degradation in different pathologies.
Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling
Yuan, Xiao-Yu,Fu, Ding-Yi,Ren, Xing-Feng,Fang, Xuexun,Wang, Lincong,Zou, Shuxue,Wu, Yuqing
supporting information, p. 5847 - 5852 (2013/09/12)
As a new type of cathepsin K inhibitor, azadipeptide nitriles have the characteristics of proteolytic stability and excellent inhibitory activity, but they exhibit barely any satisfactory selectivity. Great efforts have focused on improving their selectivity toward cathepsin K. In this sequential study, we report the further structural optimization, synthesis, molecular modeling, and in vitro enzymatic assays of a new series of potent and selective inhibitors of cathepsin K without the P2-P3 amide linker. Significant selective improvements were achieved for cathepsin K over L, S and B, and a triaryl meta-product 13′ possessed the favorable balance between potency (Ki = 0.29 nM) and selectivity of cathepsin K over cathepsin L (320-fold), S (1784-fold) and B (8566-fold). We undertook a covalent protein-ligand docking study to explain the improved selectivity of several representative compounds. Such a selectivity improvement would be useful to avoid harmful side effects in practical applications of these compounds.
Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease
Chen, Jian Jeffrey,Qian, Wenyuan,Biswas, Kaustav,Yuan, Chester,Amegadzie, Albert,Liu, Qingyian,Nixey, Thomas,Zhu, Joe,Ncube, Mqhele,Rzasa, Robert M.,Chavez, Frank,Chen, Ning,Demorin, Frenel,Rumfelt, Shannon,Tegley, Christopher M.,Allen, Jennifer R.,Hitchcock, Stephen,Hungate, Randy,Bartberger, Michael D.,Zalameda, Leeanne,Liu, Yichin,McCarter, John D.,Zhang, Jianhua,Zhu, Li,Babu-Khan, Safura,Luo, Yi,Bradley, Jodi,Wen, Paul H.,Reid, Darren L.,Koegler, Frank,Dean Jr., Charles,Hickman, Dean,Correll, Tiffany L.,Williamson, Toni,Wood, Stephen
supporting information, p. 6447 - 6454 (2013/11/19)
γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
UREA COMPOUNDS AS GAMMA SECRETASE MODULATORS
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Page/Page column 56, (2010/01/29)
The present invention provides compounds Formula (I) that are gamma secretase modulators and are therefore useful for the treatment of diseases treatable by modulation of gamma secretase such as Alzheimer's disease. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
GAMMA SECRETASE MODULATORS
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Page/Page column 107, (2009/07/17)
The present invention provides compounds that are gamma secretase modulators and are therefore useful for the treatment of diseases treatable by modulation of gamma secretase such as Alzheimer's disease. Also provided are pharmaceutical compositions conta
A novel class of nonpeptidic biaryl inhibitors of human cathepsin K
Robichaud, Jo?l,Oballa, Renata,Prasit, Peppi,Falgueyret, Jean-Pierre,Percival, M. David,Wesolowski, Gregg,Rodan, Sevgi B.,Kimmel, Donald,Johnson, Colena,Bryant, Cliff,Venkatraman, Shankar,Setti, Eduardo,Mendonca, Rohan,Palmer, James T.
, p. 3709 - 3727 (2007/10/03)
A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC50 = 3 nM) that is selective versus cathepsins B (IC50 = 3950 nM), L (IC50 = 3725 nM), and S (IC50 = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC 50 of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.
Practical asymmetric synthesis of a potent Cathepsin K inhibitor. Efficient palladium removal following Suzuki coupling
Chen, Cheng-yi,Dagneau, Philippe,Grabowski, Edward J.J.,Oballa, Renata,O'Shea, Paul,Prasit, Peppi,Robichaud, Joel,Tillyer, Rich,Wang, Xin
, p. 2633 - 2638 (2007/10/03)
A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthe
