Dioxo-triazines as a novel series of cathepsin K inhibitors

Rankovic, Zoran; Cai, Jiaqiang; Fradera, Xavier; Dempster, Maureen; Mistry, Ashvin; Mitchell, Ann; Long, Clive; Hamilton, Emma; King, Angela G.; Boucharens, Sylviane; Jamieson, Craig; Gillespie, Jonathan; Cumming, Iain; Uitdehaag, Joost C.M.; Zeeland, M. van

doi:10.1016/j.bmcl.2010.01.116

Cited by 26 publications

(9 citation statements)

References 15 publications

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“…The biological activities of 1,2,4-triazines have attracted the attention of many chemists because numerous 1,2,4-triazines are biologically active [ 12 , 13 , 14 , 15 , 16 , 17 ] and are used in medicine, especially as anti AIDS agents, anticancer agents [ 18 , 19 ], antitubercular agents [ 20 ], potent CRF receptor antagonists [ 21 ], cathepsin K inhibitors [ 22 ], and for their anti-anxiety and anti-inflammatory activities [ 23 , 24 ], as well as in agriculture [ 25 , 26 , 27 , 28 ]. They also form complexes with metal ions which are used for metal determination.…”

Section: Introductionmentioning

confidence: 99%

Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity

2011

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Rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2-thienyl)vinyl]-1,2,4-triazin-5(4H)-one 1 under microwave irradiation is described. Some new fused heterobicyclic nitrogen systems such as 1,2,4-triazino[3,4-b][1,3,4]thiadiazinones, 1,3,4-thiadiazolo[2,3-c][1,2,4]triazinone and pyrazolo[5,1-c]-[1,2,4]triazine-7-carbonitrile, have been synthesized by treatment of 1 with bifunctional oxygen and halogen compounds, CS2/KOH and malononitrile via heterocyclization reactions, in addition to some uncondensed triazines. Structures of the products have been deduced from their elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR). Select new synthesized compounds were screened as anticancer agents, with some showing activity as cytotoxic agents against different cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity

2011

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“…As reported previously, some 4‐arylazo‐3,5‐diaminopyrazoles were proven to be efficient cyclin‐dependent kinase (CDK) inhibitors16 and numerous 1‐aryl‐6‐azauracils were identified as cathepsin K inhibitors 17. Therefore, we focused our attention on the synthesis of codeine heterocyclic derivatives 9 and 11 (Scheme ).…”

Section: Resultsmentioning

confidence: 98%

Synthesis of 1‐Aminocodeine as a Synthon for Other Codeine Derivatives

et al. 2013

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The first nitration of codeine by using bismuth nitrate pentahydrate under mild reaction conditions is described. The resulting 1‐nitrocodeine was reduced to 1‐aminocodeine, a key precursor for the synthesis of the azo derivative and several hydrazones. Structures of both 1‐nitrocodeine and 1‐aminocodeine were unequivocally determined by single‐crystal X‐ray analysis. The reported preliminary synthetic study lays the groundwork for the synthesis of modified codeine derivatives with potential biological activity.

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“…We found an intriguing 3D structural overlap between the −CF 3 of 2 and the −CF3 of a potent series of covalent 1 H -imidazo[4,5- c ]pyridine-4-carbonitrile inhibitors, represented by the X-ray structure of compound 46 (Cpd46) bound to CatS with an IC 50 value of 10 nM (Figure ). These imidazo[4,5- c ]pyridine inhibitors were derived from a related series of (3-trifluoromethyl-phenyl)pyrimidine-2-carbonitriles and 6-cyano-2-(3′-trifluoromethyl-phenyl)-3,5-dioxo-1,2,4-triazines, for which the −CF3 group was essential for potency. , This suggests that −CF3 is a privileged interaction partner for this hotspot of the CatS substrate-binding surface and that our noncovalent fragment hit 2 picked up this hotspot. Although the nonpeptidic composition of these potent carbonitriles is attractive, we had safety concerns about their potentially reactive warhead and did not follow up on this merging opportunity.…”

Section: Resultsmentioning

confidence: 99%

Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors

et al. 2020

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Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure–activity relationship enabled efficient potency optimization.

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Dioxo-triazines as a novel series of cathepsin K inhibitors

Cited by 26 publications

References 15 publications

Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity

Microwave Assisted Synthesis of Some New Fused 1,2,4-Triazines Bearing Thiophene Moieties With Expected Pharmacological Activity

Synthesis of 1‐Aminocodeine as a Synthon for Other Codeine Derivatives

Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors

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