- Microscale Parallel Synthesis of Acylated Aminotriazoles Enabling the Development of Factor XIIa and Thrombin Inhibitors
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Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.
- Platte, Simon,Korff, Marvin,Imberg, Lukas,Balicioglu, Ilker,Erbacher, Catharina,Will, Jonas M.,Daniliuc, Constantin G.,Karst, Uwe,Kalinin, Dmitrii V.
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supporting information
p. 3672 - 3690
(2021/08/07)
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- Acylated 1 H-1,2,4-Triazol-5-Amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action
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We herein report the conventional and microscale parallel synthesis of selective inhibitors of human blood coagulation factor XIIa and thrombin exhibiting a 1,2,4-Triazol-5-Amine scaffold. Structural variations of this scaffold allowed identifying derivative 21i, a potent 29 nM inhibitor of FXIIa, with improved selectivity over other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time, acylated 1,2,4-Triazol-5-Amines were proved to have anticoagulant properties and the ability to affect thrombin-And cancer-cell-induced platelet aggregation. Performed mass spectrometric analysis and molecular modeling allowed us to discover previously unknown interactions between the synthesized inhibitors and the active site of FXIIa, which uncovered the mechanistic details of FXIIa inhibition. Synthesized compounds represent a promising starting point for the development of novel antithrombotic drugs or chemical tools for studying the role of FXIIa and thrombin in physiological and pathological processes.
- Korff, Marvin,Imberg, Lukas,Will, Jonas M.,Bückrei?, Nico,Kalinina, Svetlana A.,Wenzel, Benjamin M.,Kastner, Gregor A.,Daniliuc, Constantin G.,Barth, Maximilian,Ovsepyan, Ruzanna A.,Butov, Kirill R.,Humpf, Hans-Ulrich,Lehr, Matthias,Panteleev, Mikhail A.,Poso, Antti,Karst, Uwe,Steinmetzer, Torsten,Bendas, Gerd,Kalinin, Dmitrii V.
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supporting information
p. 13159 - 13186
(2020/11/13)
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- triAZOLOtriAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyperfunctioning, such as certain types cancers. Compounds of formula (1) and methods of preparing the compounds are disclosed in the invention.
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Page/Page column 129
(2020/01/24)
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- TRIAZOLOTRIAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyp
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Page/Page column 49
(2020/01/24)
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- 3-Aryl/Heteroaryl-5-amino-1-(3′,4′,5′-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization
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Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3′,4′,5′-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50 50 values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC50 value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC50 = 1.3 μM).
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Bortolozzi, Roberta,Viola, Giampietro
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p. 361 - 374
(2018/07/13)
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- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
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There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
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Paragraph 0229-0233
(2017/12/07)
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- MULTISUBSTITUTED AROMATIC COMPOUNDS AS SERINE PROTEASE INHIBITORS
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There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of kallikrein, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of kallikrein.
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Paragraph 0210
(2014/09/29)
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- Synthesis of 3-pyridyl-substituted 5-amino-1,2,4-triazoles from aminoguanidine and pyridinecarboxylic acids
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Effect of the molar ratio between reagents, temperature, and synthesis duration on the yield of 3-pyridylsubstituted 5-amino-1,2,4-triazoles in the reaction of aminoguanidine hydrochloride with pyridinecarboxylic acids under acid catalysis conditions was studied. A single-reactor method for synthesis of 3-pyridyl-substituted 5-amino-1,2,4-triazoles and their hydrochlorides was developed.
- Chernyshev,Tarasova,Chernysheva,Taranushich
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experimental part
p. 1890 - 1896
(2012/03/12)
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- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
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There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
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Page/Page column 66
(2011/10/31)
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- An aqueous medium synthesis and tautomerism study of 3(5)-amino-1,2,4-triazoles
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A catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous medium was performed using conventional heating and microwave irradiation. The tautomerism in the products was investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1H-forms, the 4H-form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from the established relationship were also identified.
- Dolzhenko, Anton V.,Pastorin, Giorgia,Dolzhenko, Anna V.,Chui, Wai Keung
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experimental part
p. 2124 - 2128
(2009/07/26)
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- Bioisosteric Design of Conformationally Restricted Pyridyltriazole Histamine H2-Receptor Antagonists
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A process of bioisosteric drug design is described whereby, in a manner analogous to synthesis, key portions of an effector molecule are successively replaced by pharmacophores or bioisosteres.This process, when applied to histamine, leads to the competitive histamine H2-receptor antagonist prototype 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (7).The biaryl nature of 7 fixes internitrogen distances, and comparison of these with histamine suggests that 7 shares structural features more in common with histamine trans rather than histamine gauche conformations.Alkylation of the prototype pyridylamino group in 7 markedly improves both histamine H2-receptor antagonist and gastric acid antisecretory activity so that the resulting agent, 3-amino-5--1,2,4-triazole (8), is more active than cimetidine.
- Lipinski, Christopher A.
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