Conformationally Constrained 1,3-Diamino Ketones:  A Series of Potent Inhibitors of the Cysteine Protease Cathepsin K

Marquis, Robert W.; Yamashita, Dennis S.; Ru, Yu; LoCastro, Stephen M.; Oh, Hye-Ja; Erhard, Karl F.; DesJarlais, Renée L.; Head, Martha S.; Smith, Ward W.; Zhao, Baoguang; Janson, Cheryl A.; Abdel-Meguid, Sherin S.; Tomaszek, Thaddeus A.; Levy, Mark A.; Veber, Daniel F.

doi:10.1021/jm980295f

Cited by 51 publications

(33 citation statements)

References 21 publications

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“…We and others have shown that functional knockout of the enzyme in the mouse results in significant osteopetrosis (5, 6) . Finally, antisense DNA as well as synthetic inhibitors of cathepsin K have been shown to inhibit bone resorption in vitro and in vivo in rodents 7‐11) . All these data show an essential role for this enzyme in bone resorption and suggest that cathepsin K inhibition may be a viable treatment for diseases associated with elevated bone turnover.…”

Section: Introductionmentioning

confidence: 83%

Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Stroup

Lark

Veber

et al. 2001

Journal of Bone and Mineral Research

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147

111

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Section: Introductionmentioning

confidence: 83%

Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Stroup

Lark

Veber

et al. 2001

Journal of Bone and Mineral Research

Self Cite

147

111

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“…Based on this information, we designed protease inhibitors that contain a central electrophile surrounded by aliphatic amino acid residues. Previously, Veber and co-workers (21,22) found that symmetrical ketone derivatives served as potent inhibitors of the cysteine protease cathepsin K. These compounds bind to the enzyme such that the peptide portions of the molecules on either side of the ketone electrophile occupy both the prime and non-prime binding sites. We reasoned that analogs of these compounds might be well suited for mimicking the hydrophobic core of the signal peptide and, therefore, might serve as potent inhibitors of the putative signal peptide peptidase activity.…”

Section: Synthesis Of Peptide Ketonementioning

confidence: 99%

Release of Signal Peptide Fragments into the Cytosol Requires Cleavage in the Transmembrane Region by a Protease Activity That Is Specifically Blocked by a Novel Cysteine Protease Inhibitor

Weihofen

Lemberg

Ploegh³

et al. 2000

Journal of Biological Chemistry

116

131

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Signal peptides of secretory and membrane proteins are generated by proteolytic processing of precursor proteins after insertion into the endoplasmic reticulum membrane. Liberated signal peptides can be further processed, and the resulting N-terminal fragments are released toward the cytosol, where they may interact with target proteins like calmodulin. We show here that the processing of signal peptides requires a protease activity distinct from signal peptidase. This activity is inhibited specifically with a newly developed cysteine protease inhibitor, 1,3-di-(N-carboxybenzoyl-L-leucyl-Lleucyl)amino acetone ((Z-LL) 2 ketone). Inhibitor studies revealed that the final, (Z-LL) 2 ketone-sensitive cleavage event occurs within the hydrophobic transmembrane region of the signal peptide, thus promoting the release of an N-terminal fragment into the cytosol.

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“…Several studies have shown that Cat K deficiency leads to an increase in bone mineral density (BMD) (5). Recent reports on the inhibition of Cat K have focused on derivatives of aldehydes (6), amino methyl ketones (7–9), hydroxymethyl ketones (10), ketobenzoxazoles (11), and most recently nitriles (12–14).…”

mentioning

confidence: 99%

Virtual Screening of Cathepsin K Inhibitors Using Docking and Pharmacophore Models

Ravikumar¹,

Pavan²,

Santhosh³

et al. 2008

Chem Biol Drug Des

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Cathepsin K is a lysosomal cysteine protease that is highly and selectively expressed in osteoclasts, the cells which degrade bone during the continuous cycle of bone degradation and formation. Inhibition of cathepsin K represents a potential therapeutic approach for diseases characterized by excessive bone resorption such as osteoporosis. In order to elucidate the essential structural features for cathepsin K, a three-dimensional pharmacophore hypotheses were built on the basis of a set of known cathepsin K inhibitors selected from the literature using catalyst program. Several methods are used in validation of pharmacophore hypothesis were presented, and the fourth hypothesis (Hypo4) was considered to be the best pharmacophore hypothesis which has a correlation coefficient of 0.944 with training set and has high prediction of activity for a set of 30 test molecules with correlation of 0.909. The model (Hypo4) was then employed as 3D search query to screen the Maybridge database containing 59,000 compounds, to discover novel and highly potent ligands. For analyzing intermolecular interactions between protein and ligand, all the molecules were docked using Glide software. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme inhibitor interaction pattern identified from molecular docking.

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Conformationally Constrained 1,3-Diamino Ketones: A Series of Potent Inhibitors of the Cysteine Protease Cathepsin K

Cited by 51 publications

References 21 publications

Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Potent and Selective Inhibition of Human Cathepsin K Leads to Inhibition of Bone Resorption In Vivo in a Nonhuman Primate

Release of Signal Peptide Fragments into the Cytosol Requires Cleavage in the Transmembrane Region by a Protease Activity That Is Specifically Blocked by a Novel Cysteine Protease Inhibitor

Virtual Screening of Cathepsin K Inhibitors Using Docking and Pharmacophore Models

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