Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Rankovic, Zoran; Cai, Jiaqiang; Kerr, Jennifer; Fradera, Xavier; Robinson, John; Mistry, Ashvin; Hamilton, Emma; McGarry, George; Andrews, Fiona; Caulfield, Wilson; Cumming, Iain; Dempster, Maureen; Waller, John; Scullion, Paul; Martin, Iain; Mitchell, Ann; Long, Clive; Baugh, Mark; Westwood, Paul; Kinghorn, Emma; Bruin, John; Hamilton, William; Uitdehaag, Joost C.M.; Zeeland, M. van; Potin, Dominique; Sanière, Laurent; Fouquet, Andre; Chevallier, F; Deronzier, Hortense; Dorleans, Cecile; Nicolaï, Eric

doi:10.1016/j.bmcl.2010.01.100

Cited by 24 publications

(24 citation statements)

References 18 publications

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“…Unfortunately, no potencies are quoted. This series is probably 'drug-like' since the 2-cyanopyrimidine warhead, which is known to form reversible covalent bonds with active site cysteine residues [77], has clinical precedent from the Novartis cathepsin K inhibitor dutacatib (AFG495) 17 which reached a Phase I osteoporosis trial [78].…”

Section: Usp2mentioning

confidence: 99%

Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Kemp¹

2016

Progress in Medicinal Chemistry

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Section: Usp2mentioning

confidence: 99%

Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Kemp¹

2016

Progress in Medicinal Chemistry

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“…Based on the results from these screens, three compounds, CP673854, CP989759, and CP725567, were selected as confirmed in vitro leads. The nitrile (CP673854) and the thiosemicarbazone (CP989759) are members of classes of compounds already known to contain cysteine peptidase inhibitors (15,33), although not previously tested against EtCatB. To the best of our knowledge, the oxazolone scaffold of CP725567 is a novel cysteine peptidase inhibitor scaffold that has not been reported before.…”

Section: Figmentioning

confidence: 99%

Identification of Lead Compounds Targeting the Cathepsin B-Like Enzyme of Eimeria tenella

Schaeffer

Schroeder²,

Heckeroth³

et al. 2012

Antimicrob Agents Chemother

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Cysteine peptidases have been implicated in the development and pathogenesis of Eimeria. We have identified a single-copy cathepsin B-like cysteine peptidase gene in the genome database of Eimeria tenella (EtCatB). Molecular modeling of the predicted protein suggested that it differs significantly from host enzymes and could be a good drug target. EtCatB was expressed and secreted as a soluble, active, glycosylated mature enzyme from Pichia pastoris. Biochemical characterization of the recombinant enzyme confirmed that it is cathepsin B-like. Screening of a focused library against the enzyme identified three inhibitors (a nitrile, a thiosemicarbazone, and an oxazolone) that can be used as leads for novel drug discovery against Eimeria. The oxazolone scaffold is a novel cysteine peptidase inhibitor; it may thus find widespread use.

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“…A thioimidate moiety formed by covalent interaction between the nitrile warhead and the C26 thiolate in the CPB2.8∆CTE catalytic site was assumed and generated for the covalent docking procedure (Figure 3B) [36]. The cyclohexyl group is placed into the hydrophobic S 2 subsite while the 2-methoxy-pyridyl moiety occupies the S 1 ’ subsite.…”

Section: Resultsmentioning

confidence: 99%

Identification of Semicarbazones, Thiosemicarbazones and Triazine Nitriles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

et al. 2013

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Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas’ disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases.

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Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors

Cited by 24 publications

References 18 publications

Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Identification of Lead Compounds Targeting the Cathepsin B-Like Enzyme of Eimeria tenella

Identification of Semicarbazones, Thiosemicarbazones and Triazine Nitriles as Inhibitors of Leishmania mexicana Cysteine Protease CPB

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