- Transformation of a selective factor Xa inhibitor rivaroxaban into a dual factor Xa/thrombin inhibitor by modification of the morpholin-3-one moiety
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Replacement of the P4 morpholin-3-one moiety in a selective factor Xa inhibitor rivaroxaban by 2-ethoxycarbonylpiperidine resulted in a dual factor Xa/thrombin inhibitor 24, possessing a Ki of 62 ± 18 nM for factor Xa and a Ki/
- Trstenjak, Uros,Ilas, Janez,Kikelj, Danijel
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- Design, synthesis, and biological evaluation of cyano-substituted 2,4-diarylaminopyrimidines as potent JAK3 inhibitors for the treatment of B-cell lymphoma
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A series of cyano-substituted 2,4-diarylaminopyrimidines was designed and synthesized as potent non-covalent JAK3 inhibitors. Among the derivatives synthesized, 9o (IC50 = 22.86 nM), 9 k (IC50 = 21.58 nM), and 9j (IC50 = 20.66 nM) demonstrated inhibitory potencies against JAK3 similar to the known JAK3 inhibitor tofacitinib (IC50 = 20.10 nM). Moreover, 9o displayed potent anti-proliferative activities against Raji and Ramos cells, with IC50 values of 0.9255 μM and 1.405 μM, respectively. In addition, 9o demonstrated low toxicity in normal HBE (human bronchial epithelial cells, IC50 > 10 μΜ) and L-02 (human liver cells, IC50 = 3.104 μΜ) cells. Analysis of the mode of action by flow cytometry indicated that 9o effectively arrested Raji cells at the G2/M phase. Taken together, these results suggested that 9o might be a promising candidate for development as a potential treatment for B-cell lymphoma.
- Chen, Lixue,Deng, Tuo,Jin, Yue,Li, Yanxia,Ma, Xiaodong,Wang, Changyuan,Wu, Bin,Xu, Youjun,Yang, Song,Yu, Jiawen
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- New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase
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Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
- Zidar, Nace,Toma?i?, Tihomir,Macut, Helena,Sirc, Anja,Brvar, Matja?,Montalv?o, Sofia,Tammela, P?ivi,Ila?, Janez,Kikelj, Danijel
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supporting information
p. 197 - 211
(2016/04/26)
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- PDE 10a Inhibitors for the Treatment of Type II Diabetes
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Disclosed are compounds, compositions and methods for treating Type II diabetes. Such compounds are represented by Formula (I) as follows: wherein R1, R2, L, and Q are defined herein.
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Paragraph 0563-0565
(2015/01/06)
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- PDE 10a Inhibitors for the Treatment of Type II Diabetes
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Disclosed are compounds, compositions and methods for treating Type II diabetes. Such compounds are represented by Formula (I) as follows: wherein R1, R2, L, and Q are defined herein.
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Paragraph 0837; 0838
(2015/01/06)
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- Synthesis and biological evaluation of direct thrombin inhibitors bearing 4-(piperidin-1-yl)pyridine at the P1 position with potent anticoagulant activity
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The design and synthesis of a new class of nonpeptide direct thrombin inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure-activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (K i = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg-1), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (P 0.05).
- De Candia, Modesto,Fiorella, Filomena,Lopopolo, Gianfranco,Carotti, Andrea,Romano, Maria Rosaria,Lograno, Marcello Diego,Martel, Sophie,Carrupt, Pierre-Alain,Belviso, Benny D.,Caliandro, Rocco,Altomare, Cosimo
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p. 8696 - 8711
(2013/12/04)
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- Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores
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Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa an
- Trstenjak, Uro?,Ila?, Janez,Kikelj, Danijel
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p. 302 - 313
(2013/07/27)
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- PIPERAZINE COMPOUND CAPABLE OF INHIBITING PROSTAGLANDIN D SYNTHASE
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This invention relates to a piperazine compound represented by Formula (I), wherein R1 is C1-6 alkyl;R2 is hydroxy, C1-6 alkyl that may have one or more substituents, —(C═O)—N(R3)(R4), or —(C═O)—OR5;R3 and R4 are the same or different, and each represents hydrogen or C1-6 alkyl that may have one or more substituents, orR3 and R4, taken together with a nitrogen atom to which R3 and R4 are attached, may form a saturated heterocyclic group;R5 is hydrogen or C1-6 alkyl that may have one or more substituents; andn is 1 or 2;or a salt thereof.
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Page/Page column 11
(2012/01/13)
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- 1, 4-DISUBSTITUTED PIPERIDINES AS VASOPRESSIN RECEPTOR VIA ANTAGONISTS
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The present invention provides compounds of formula (1) compositions comprising such compounds; the use of such compounds in therapy (such as in the treatment of dysmenorrhoea); and methods of treating patients with such compounds; wherein A and G are as defined herein.
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Page/Page column 40; 43
(2010/09/17)
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- Inhibitors of Diacylglycerol Acyltransferase
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Provided herein are amides containing at least a four ring structure, which are inhibitors of diacylglycerol acyltransferase and are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.
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Page/Page column 13
(2010/06/22)
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- RETROMETABOLIC COMPOUNDS
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The present invention relates to phenylaminopyrimidine compounds that are retrometabolic drugs or metabolites thereof. These compounds are also inhibitors of protein kinases including JAK kinases, in particular JAK2 kinases and can be used in the treatmen
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Page/Page column 58
(2009/04/25)
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- UREA DERIVATIVE
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The present invention relates to a urea derivative or a pharmacologically acceptable salt thereof having an excellent DGAT inhibitory effect. A urea derivative having the formula: [wherein R 1 is a C 6 -C 10 aryl group which may be independently mono- to pentasubstituted by a group selected from Substituent Group a or others; R 2 is a C 6 -C 10 aryl group which may be independently mono- to pentasubstituted by a group selected from Substituent Group a or others; E is a group having the formula (II) or the formula (III) (wherein R 3 is a hydrogen atom or others; R 4 and R 5 , which are the same or different, are a hydrogen atom or others; X and U, which are the same or different, are a group represented by the formula CH or others; m and n, which are the same or different, are 1 or another number) or others; and A is a group represented by the formula -NH-C(=O)- or others], or a pharmacologically acceptable salt thereof.
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Page/Page column 148
(2010/11/26)
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- N-ARYL PIPERIDINE SUBSTITUTED BIPHENYLCARBOXAMIDES
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N-aryl piperidine substituted biphenylcarboxamides compounds of formula (I), methods for preparing compounds, pharmaceutical compositions comprising said compounds as wee as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.
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Page/Page column 23
(2010/02/12)
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