- Design, synthesis, and evaluation of potent RIPK1 inhibitors with in vivo anti-inflammatory activity
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RIPK1 plays a key role in the necroptosis pathway that regulates inflammatory signaling and cell death in various diseases, including inflammatory and neurodegenerative diseases. Herein, we report a series of potent RIPK1 inhibitors, represented by compound 70. Compound 70 efficiently blocks necroptosis induced by TNFα in both human and mouse cells (EC50 = 17–30 nM). Biophysical assay demonstrates that compound 70 potently binds to RIPK1 (Kd = 9.2 nM), but not RIPK3 (Kd > 10,000 nM). Importantly, compound 70 exhibits greatly improved metabolic stability in human and rat liver microsomes compared to compound 6 (PK68), a RIPK1 inhibitor reported in our previous work. In addition, compound 70 displays high permeability in Caco-2 cells and excellent in vitro safety profiles in hERG and CYP assays. Moreover, pre-treatment of 70 significantly ameliorates hypothermia and lethal shock in SIRS mice model. Lastly, compound 70 possesses favorable pharmacokinetic parameters with moderate clearance and good oral bioavailability in SD rat. Taken together, our work supports 70 as a potent RIPK1 inhibitor and highlights its potential as a prototypical lead for further development in necroptosis-associated inflammatory disorders.
- Li, Zhanhui,Hao, Yongjin,Yang, Chengkui,Yang, Qing,Wu, Shuwei,Ma, Haikuo,Tian, Sheng,Lu, Haohao,Wang, Jingrui,Yang, Tao,He, Sudan,Zhang, Xiaohu
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- Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors
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Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5-phenyl triazolopyrimidine regioisomer 7a. Subsequent structure–activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5-phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC50 50 μM), with 17z showing excellent cell permeability and no cytotoxicity.
- Ribeiro, Carlos J.A.,Kankanala, Jayakanth,Xie, Jiashu,Williams, Jessica,Aihara, Hideki,Wang, Zhengqiang
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supporting information
p. 257 - 261
(2018/12/11)
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- METHOD FOR PREPARING SUBSTITUTED TRIAZOLOPYRIDINES
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The present invention relates to methods of preparing substituted triazolopyridine compounds of general formula (I) as described and defined herein, as well as to intermediate compounds useful in the preparation of said compounds.
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Paragraph 0321-0324
(2015/06/03)
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- METHOD FOR PREPARING SUBSTITUTED TRIAZOLOPYRIDINES
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The present invention relates to methods o f preparing substituted triazolopyridine compounds of general formula (I) as described and defined herein, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 69
(2014/02/15)
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- COMBINATIONS FOR THE TREATMENT OF CANCER
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The present invention relates to combinations of at least two compounds A and B, compound A being an inhibitor of Mps-1 kinase, and compound B being an inhibitor of an anti-apoptotic protein of the Bcl-2 family. Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease, particularly for the treatment of cancer. Another aspect of the present invention relates to the use of an anti- apoptotic protein from the Bcl-2 family as a sensitizer of cells to Mps-1 inhibitors. Another aspect of the present invention relates to the use of the ratio of pro-apoptotic and anti-apoptotic proteins from the Bcl-2 family in a biological sample as a biomarker for a Mps-1 kinase inhibitor treatment.
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Page/Page column 126
(2014/02/16)
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- SUBSTITUTED TRIAZOLOPYRIDINES HAVING ACTIVITY AS MPS-1 INHIBITORS
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The present invention relates to substituted triazolopyridine compounds of general formula (I), in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 96
(2015/01/06)
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- PRODRUG DERIVATIVES OF SUBSTITUTED TRIAZOLOPYRIDINES
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The present invention relates to prodrug derivatives of Mps-1 kinase inhibitors, processes for their preparation, and their use for the treatment and/or prophylaxis of diseases.
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Page/Page column 71; 72
(2015/01/09)
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- TRIAZOLOPYRIDINE COMPOUNDS AS PDE10A INHIBITORS
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The invention is concerned with triazolopyridine compounds of formula (I) wherein R1, R2 and R3 are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds inhi
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Page/Page column 35
(2013/04/10)
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- SUBSTITUTED TRIAZOLOPYRIDINES AND THEIR USE AS TTK INHIBITORS
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The present invention relates to substituted triazolopyndine compounds of general formula (I) : in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 93
(2013/07/05)
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- UREA DERIVATIVE HAVING PI3K INHIBITORY ACTIVITY
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Provided is a compound or a pharmaceutically acceptable salt thereof which inhibits the activity of PI3K to regulate many biological processes including the growth, differentiation, survival, proliferation, migration, metabolism, and the like of cells and is therefore useful for the prophylaxis/therapy of diseases including inflammatory diseases, arteriosclerosis, vascular/circulatory diseases, cancer/tumors, immune system diseases, cell proliferative diseases, infectious diseases, and the like. The above problem was solved by providing a urea derivative shown in the present specification, or a pharmaceutically acceptable salt thereof.
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Page/Page column 113
(2012/03/26)
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- PEPTIDASE INHIBITORS
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Novel compounds of the formula (I) wherein R1, R2, D, A, B and X have the meanings defined herein, pharmaceutical compositions comprising them as active ingredient, as well as their use in medicine, in particular as peptidase inhibitors, more specifically
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Page/Page column 130
(2012/10/18)
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- SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors
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Herein we describe the SAR of a novel series of 6-aryl-2-amino- triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion a
- Bell, Kathryn,Sunose, Mihiro,Ellard, Katie,Cansfield, Andrew,Taylor, Jess,Miller, Warren,Ramsden, Nigel,Bergamini, Giovanna,Neubauer, Gitte
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scheme or table
p. 5257 - 5263
(2012/09/07)
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- TRIAZOLOPYRIDINES
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The present invention relates to triazolopyridine compounds of general formula (I) : in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said com
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Page/Page column 72-73
(2012/11/07)
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- SUBSTITUTED TRIAZOLOPYRIDINES
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The present invention relates to substituted triazolopyridine compounds of general formula (I) : in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease such as tumours and proliferative diseases, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 69
(2012/12/13)
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- TRIAZOLOPYRIDINE DERIVATIVES
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The present invention relates to triazolopyridine compounds of general formula (I) which are Monopolar Spindle 1 kinase (Mps-1 or TTK) inhibitors in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of proliferative diseases, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 63
(2011/06/23)
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- TRIAZOLOPYRIDINES
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The present invention relates to triazolopyridine compounds of general formula (I) which are Monopolar Spindle 1 kinase (Mps-1 or TTK) inhibitors: Formula (I), in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis proliferative of diseases, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 53
(2011/06/23)
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- Triazolopyridine derivates
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The present invention relates to triazolopyridine compounds of general formula (I) which are Monopolar Spindle 1 kinase (Mps-1 or TTK) inhibitors: in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of proliferative diseases, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 23
(2011/08/03)
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- Triazolopyridines
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The present invention relates to triazolopyridine compounds of general formula (I) which are Monopolar Spindle 1 kinase (Mps-1 or TTK) inhibitors: in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of proliferative diseases, as well as to intermediate compounds useful in the preparation of said compounds.
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Page/Page column 25
(2011/08/03)
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- SUBSTITUTED TRIAZOLOPYRIDINES
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The present invention relates to substituted triazolopyridine compounds of general formula (I) : in which R1, R2, R3, R4, and R5 are as given in the description and in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds, to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease of uncontrolled cell growth, proliferation and/or survival as well as to the use of intermediate compounds for the preparation of said compounds.
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Page/Page column 92
(2012/01/06)
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- Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3
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New drugs are urgently needed for the treatment of tropical parasitic diseases such as leishmaniasis and human African trypanosomiasis (HAT). This work involved a high-throughput screen of a focussed kinase set of ~3400 compounds to identify potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin6 complex. The aim of this study is to provide chemical validation that Leishmania CRK3-CYC6 is a drug target. Eight hit series were identified, of which four were followed up. The optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin dependent kinase CDK2. Selective at last: [1,2,4]Triazolo[1,5-a]pyridines, aminopyrazoles, and disubstituted ureas were explored as potent and parasite-selective inhibitors of an enzymatic Leishmania CRK3-cyclin6 complex. Optimisation of these series using classical SAR studies afforded low-nanomolar CRK3 inhibitors with significant selectivity over the closely related human cyclin-dependent kinase CDK2.
- Cleghorn, Laura A.T.,Woodland, Andrew,Collie, Iain T.,Torrie, Leah S.,Norcross, Neil,Luksch, Torsten,Mpamhanga, Chido,Walker, Roderick G.,Mottram, Jeremy C.,Brenk, Ruth,Frearson, Julie A.,Gilbert, Ian H.,Wyatt, Paul G.
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scheme or table
p. 2214 - 2224
(2012/04/17)
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- PREPARATION AND USES OF 1,2,4-TRIAZOLO [1,5a] PYRIDINE DERIVATIVES
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This application relates to compounds of the general Formula I and salts thereof, wherein X, R1A, R1B, R2, R3, R4, and R5 are as defined herein. The application also relates to compositions and methods of treatment of hyperproliferative diseases or disorders.
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Page/Page column 155
(2010/12/29)
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- METHODS FOR THE IDENTIFICATION OF PHOSPHATIDYLINOSITOL KINASE INTERACTING MOLECULES AND FOR THE PURIFICATION OF PHOSPHATIDYLINOSITOL KINASE PROTEINS
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The present invention relates to immobilization compounds of formula (I), immobilization products and preparations thereof as well as methods and uses for the identification of phosphatidylinositol kinase interacting compounds or for the purification or identification of phosphatidylinositol kinase proteins.
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Page/Page column 33-34
(2010/12/18)
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- SUBSTITUTED 5-AMINOPYRAZOLES AND USE THEREOF
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The present application relates to novel substituted 5-aminopyrazoles, methods of production thereof, use thereof alone or in combinations for the treatment and/or prophylaxis of diseases and use thereof for the production of medicinal products for the treatment and/or prophylaxis of diseases.
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Page/Page column 126
(2010/04/03)
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- FUSED BICYCLIC COMPOUNDS AS INHIBITORS FOR PI3 KINASE
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The invention relates to compounds of formula (I) for the regulation of phosphoinositides 3-kinases activity and related diseases.
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Page/Page column 164
(2010/09/18)
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- TRIAZOLOPYRIDINE COMPOUNDS AND THEIR USE AS ASK INHIBITORS
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The present invention relates to triazolopyridine compounds according to Formula (I), their use as medicament, for treating autoimmune disorders, inflammatorydiseases, cardiovascular disceases and/or neurodegenerative diseases and a process for their preparation.
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Page/Page column 57
(2009/04/25)
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- AMINO TRIAZOLES AS PI3K INHIBITORS
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The invention relates to compounds of formula (I) Said compounds are useful as protein kinase inhibitors, especially inhibitors of P13K, for the treatment or prophylaxis of immunological, inflammatory, autoimmune, or allergic disorders. The invention also relates to pharmaceutical compositions including said compounds, the preparation of such compounds as well as the production of and use as medicaments.
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Page/Page column 43
(2009/07/03)
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- FUSED BICYCLIC COMPOUNDS AND USE THEREOF AS PI3K INHIBITORS
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The invention relates to compounds of formula (I), for the regulation of phosphoinositides 3-kinases activity and related diseases.
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Page/Page column 85
(2009/12/05)
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- BICYCLIC HETEROARYL COMPOUNDS AND THEIR USE AS KINASE INHIBITORS
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Phosphatidylinositol (PI) 3-kinase inhibitor compounds, their pharmaceutically acceptable salts, and prodrugs thereof; compositions of the new compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases characterized by the abnormal activity of growth factors, protein serine/threonine kinases, and phospholipid kinases.
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Page/Page column 74-75
(2009/03/07)
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