β-Substituted Cyclohexanecarboxamide:  A Nonpeptidic Framework for the Design of Potent Inhibitors of Cathepsin K

Crane, Sheldon N.; Black, W. Cameron; Palmer, James T.; Davis, Dana; Setti, Eduardo L.; Robichaud, Jacques; Pâquet, Julie; Oballa, Renata M.; Bayly, Christopher I.; McKay, Daniel J.; Somoza, John R.; Chauret, Natalie; Seto, Carmai; Scheigetz, John; Wesolowski, Greg; Massé, Frédéric; Desmarais, Sylvie; Ouellet, Marc

doi:10.1021/jm051059p

Cited by 34 publications

(25 citation statements)

References 16 publications

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“…For this reason, this class of cyclic amino acids has been used in the preparation of peptide-based drugs. [36] In particular, the 1-amino cyclohexanecarboxylic acid framework has been used in the design of cathepsin K inhibitors [37] and V 2 agonists of arginine vasopressin. [38] Treatment of (À)-10 with acetic anhydride followed by treatment with TBAF in THF gave the corresponding free carboxylic acid, which in turn was coupled with glycine ethyl ester to afford dipeptide (+)-12 in good yields (Scheme 5).…”

Section: Resultsmentioning

confidence: 99%

Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

Fustero

Sánchez‐Roselló

Rodrigo

et al. 2008

Chemistry A European J

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The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was successfully adapted to solid-phase and fluorous-phase techniques. The reaction times and final deprotection were clearly more favorable in the latter, in which a fluorous trimethylsilylethanol (TMSE) tag was used. The tag was then easily removed upon treatment with TBAF in a high-yield transesterification process.

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Section: Resultsmentioning

confidence: 99%

Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

Fustero

Sánchez‐Roselló

Rodrigo

et al. 2008

Chemistry A European J

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“…As was recently described by Crane et al, these b-substituted cyclohexanecarboxamides were serendipitously discovered in an attempt to replace the P2-P3 amide bond with a methylene--thioether moiety [54]. The b-substituent bypasses the H-bond to Gly66 and bridges directly into P3.…”

Section: Wijkmans and Gossenmentioning

confidence: 91%

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

Wijkmans

Gossen

2011

Expert Opinion on Therapeutic Patents

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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.

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“…In addition, cyclic amino acids have been widely used in the preparation of peptide-based drugs. The 1-aminocyclohexanecarboxylic acid scaffold, for example, has been used in the design of a potent cathepsin K inhibitor [57] and V2 agonists of arginine vasopressin. [58] For these reasons and in view of the fact that incorporation of fluorine or fluorine-containing groups into compounds is widely used to improve the metabolic susceptibility of compounds, the synthesis of fluorinated cyclic amino acids has been receiving increasing attention in recent years.…”

Section: Fluorinated Cyclic Amino Acids (F-caas)mentioning

confidence: 99%

Recent Advances in the Synthesis of Fluorinated Amino Acids

2011

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Introduction of fluorine atoms or fluorine‐containing groups into amino acids has attracted much attention from bioorganic and medicinal chemists because the resulting fluorinated amino acids have found wide application as potential enzyme inhibitors and antitumor (antibacterial) agents. Additionally, it is well known that replacement of naturally occurring amino acid(s) in some peptide chains with their fluorinated counterparts can significantly increase specific protein–ligand or protein–protein interactions, leading to increases in the proteolytic and thermal stabilities of peptide compounds and, as a result, promote their therapeutic properties. This microreview summarizes important advances in the synthesis of fluorinated amino acids since 2005. The contents are simply divided into three groups on the basis of amino acid types: fluorinated α‐amino acids (F‐αAAs), fluorinated β‐amino acids (F‐βAAs), and fluorinated cyclic amino acids (F‐CAAs).

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β-Substituted Cyclohexanecarboxamide: A Nonpeptidic Framework for the Design of Potent Inhibitors of Cathepsin K

Cited by 34 publications

References 16 publications

Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

Solution‐, Solid‐Phase, and Fluorous Synthesis of β,β‐Difluorinated Cyclic Quaternary α‐Amino Acid Derivatives: A Comparative Study

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

Recent Advances in the Synthesis of Fluorinated Amino Acids

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