- CONJUGATES OF AMPK INHIBITORS AND PROTAC DEGRADERS AND RELATED USES
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The present disclosure relates to compounds of Formula (I): T-L-D, stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein T is an AMPK inhibiting moiety; L is a linking moiety; and D is a PROTAC degrading moiety. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK), degrading AMPK protein, and/or treat cancer in a subject.
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Paragraph 0333; 0350
(2022/01/12)
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- Yb(OTf)3catalyzed [1,3]-rearrangement of 3-alkenyl oxindoles
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A Yb(OTf)3catalyzed [1,3]-rearrangement of 3-alkenyl oxindoles was achieved, affording a variety of multifunctional 3-ylideneoxindoles with good yields andZ/Eselectivities (64%-89% yield, 78?:?22->99?:?1Z/E). Importantly, an operationally simple, one-pot sequential catalytic synthesis of 3-ylideneoxindoles was also developed. Additionally, a cross [1,3]-rearrangement experiment and nonracemic transformation were also carried out, which indicated a concerted rearrangement mechanism of this methodology.
- He, Lingchen,Hu, Xin-Gen,Jiang, Jun,Li, Juan,Li, Xinhua,Liu, Hongxin,Song, Chao,Wan, Junlin,Wu, Chaofei,Xiao, Hong-Ping
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supporting information
p. 122 - 126
(2021/12/29)
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- AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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The present disclosure relates to compounds of Formula (I): (I); stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK) and treat cancer in a subject.
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Page/Page column 72
(2021/01/23)
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- Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
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AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
- Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
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- HETEROCYCLIC COMPOUNDS, PROCESS FOR PREPARATION OF THE SAME AND USE THEREOF
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The present invention provides a heterocyclic compound represented by the formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and their use in preparing a medicament for the prevention and/or treatment of central nervous system disease.
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Paragraph 0376; 0379; 0380
(2017/07/15)
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to novel pyrrole substituted 2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-heteroarylidene-2-indolinone protein kinase inhibitors
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The present invention relates to novel 3-heteroarylidene-2-indolinone compounds and physiologically acceptable salts thereof which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- 3-(cycloalkanoheteroarylidenyl)-2-indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkano-heteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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Page column 23
(2010/02/05)
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- METHOD OF TREATING GLAUCOMA AND ISCHEMIC RETINOPATHY
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A method for treating glaucoma and ischemic retinopathy in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein n, X, Y and A
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- Method of treating psychiatric conditions
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A method for treating a psychiatic condition or disorder selected from anxiety disorders such as panic disorder, posttraumatic stress disorder and phobias, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder and mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder, schizophrenia, behavioral manifestations of mental retardation, conduct disorder or autistic disorder, dementias such as dementias of the Alzheimer's type, and dyskinesias such as drug induced and neurodegeneration based dyskinesias in a mammal, including a human, comprising administering to said mammal a pharmaceutically effective amount of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein n, X, Y and Ar are as defined above.
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- 3-(cycloalkanoheteroarylidenyl)-2- indolinone protein tyrosine kinase inhibitors
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The present invention relates to novel 3-(cycloalkanoheteroarylidenyl)-2-indolinone compounds and physiologically acceptable salts and prodrugs thereof which are expected to modulate the activity of protein tyrosine kinases and therefore to be useful in the prevention and treatment of protein tyrosine kinase related cellular disorders such as cancer.
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- Method of treating tourette's syndrome and obsessive compulsive disorder
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A method for treating Tourette's syndrome, obsessive compulsive disorder, chronic motor or vocal tic disorder in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of the formula STR1 or a pharmaceutically acceptable acid addition salt thereof, wherein n, X, Y and Ar are as defined above.
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- Method of treating tourette's syndrome
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The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Tourette's syndrome, obsessive compulsive disorder, chronic motor or vocal tic disorder in a mammal, including a human wherein n, X, Y and Ar are as defined herein.
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- 3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents
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A series of substituted phenethyl derivatives of 3- benzisothiazolylpiperazine incorporating potent D2 and 5-HT(2A) antagonist activity was investigated as an approach to a novel atypical antipsychotic agent. The in vitro profile of 8e from this series is a combination of D2 receptor affinity comparable to the typical antipsychotic agent haloperidol and a 5-HT(2A)/D2 ratio comparable to the atypical agent clozapine. In vivo 8e possesses activity consistent with an efficacious antipsychotic agent with less tendency to induce extrapyramidal side effects in man.
- Howard, Harry R.,Lowe III, John A.,Seeger, Thomas F.,Seymour, Patricia A.,Zorn, Stevin H.,Maloney, Patrick R.,Ewing, Frank E.,Newman, Michael E.,Schmidt, Anne W.,Furman, Jerome S.,Robinson, Gwendolyn L.,Jackson, Elisa,Johnson, Celeste,Morrone, Jean
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p. 143 - 148
(2007/10/03)
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- 1-Naphthylpiperazine derivatives as potential atypical antipsychotic agents
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The design and synthesis of a series of potential atypical antipsychotic agents based on the structure of 1-naphthylpiperazine are described. The incorporation of dopamine antagonist activity into the parent structure was achieved with heterocyclic surrog
- Lowe III,Seeger,Nagel,Howard,Seymour,Heym,Ewing,Newman,Schmidt,Furman,Vincent,Maloney,Robinson,Reynolds,Vinick
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p. 1860 - 1866
(2007/10/02)
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- Aryl piperazinyl-(C2 or C4) alkylene heterocyclic compounds having neuroleptic activity
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Arylpiperazinyl-ethyl(or butyl)-heterocyclic compounds and their pharmaceutically acceptable acid addition salts are neuroleptic agents. They are useful in the treatment of psychotic disorders.
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- Piperazinyl-heterocyclic compounds
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Arylpiperazinyl-ethyl(or butyl)-heterocyclic compounds and their pharmaceutically acceptable acid addition salts are neuroleptic agents. They are useful in the treatment of psychotic disorders.
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