130722-95-1Relevant articles and documents
A total synthesis of toddaquinoline exposes a dual role for cobalt in radical additions to pyridines
Harrowven,Nunn,Blumire,Fenwick
, p. 6681 - 6683 (2000)
This paper describes the first total synthesis of toddaquinoline, an alkaloid from the root bark of Formosan Toddalia asiatica. Importantly, the synthesis has exposed a dichotomy in radical reactions mediated by tin and cobalt(I) that involve additions to pyridines. Our observations suggest that cobalt plays a dual role in such reactions: Firstly initiating homolysis of the carbon to halogen bond, then acting as a Lewis acid to promote radical additions to the carbon centre adjacent to nitrogen. (C) 2000 Elsevier Science Ltd.
Piperidine and piperazine inhibitors of fatty acid amide hydrolase targeting excitotoxic pathology
Lamani, Manjunath,Malamas, Michael S.,Farah, Shrouq I.,Shukla, Vidyanand G.,Almeida, Michael F.,Weerts, Catherine M.,Anderson, Joseph,Wood, JodiAnne T.,Farizatto, Karen L.G.,Bahr, Ben A.,Makriyannis, Alexandros
supporting information, (2019/10/28)
FAAH inhibitors offer safety advantages by augmenting the anandamide levels “on demand” to promote neuroprotective mechanisms without the adverse psychotropic effects usually seen with direct and chronic activation of the CB1 receptor. FAAH is an enzyme implicated in the hydrolysis of the endocannabinoid N-arachidonoylethanolamine (AEA), which is a partial agonist of the CB1 receptor. Herein, we report the discovery of a new series of highly potent and selective carbamate FAAH inhibitors and their evaluation for neuroprotection. The new inhibitors showed potent nanomolar inhibitory activity against human recombinant and purified rat FAAH, were selective (>1000-fold) against serine hydrolases MGL and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Evaluation of FAAH inhibitors 9 and 31 using the in vitro competitive activity-based protein profiling (ABPP) assay confirmed that both inhibitors were highly selective for FAAH in the brain, since none of the other FP-reactive serine hydrolases in this tissue were inhibited by these agents. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on known FAAH cocrystal structures. To rationally design new molecules that are irreversibly bound to FAAH, we have constructed “precovalent” FAAH-ligand complexes to identify good binding geometries of the ligands within the binding pocket of FAAH and then calculated covalent docking poses to select compounds for synthesis. FAAH inhibitors 9 and 31 were evaluated for neuroprotection in rat hippocampal slice cultures. In the brain tissue, both inhibitors displayed protection against synaptic deterioration produced by kainic acid-induced excitotoxicity. Thus, the resultant compounds produced through rational design are providing early leads for developing therapeutics against seizure-related damage associated with a variety of disorders.
HETEROARYL SUBSTITUTED BETA-HYDROXYETHYLAMINES FOR USE IN TREATING HYPERGLYCAEMIA
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Page/Page column 64, (2019/04/11)
There is herein provided a compound of formula (I) or a pharmaceutically acceptable salt thereof,wherein the ring containing Q1to Q5, and the groups R1, R2 and R3, have meanings as provided in the description.
X-ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome
Kallen, Joerg,Bergsdorf, Christian,Arnaud, Bertrand,Bernhard, Mario,Brichet, Murielle,Cobos-Correa, Amanda,Elhajouji, Azeddine,Freuler, Felix,Galimberti, Ivan,Guibourdenche, Christel,Haenni, Simon,Holzinger, Sandra,Hunziker, Juerg,Izaac, Aude,Kaufmann, Markus,Leder, Lukas,Martus, Hans-Joerg,von Matt, Peter,Polyakov, Valery,Roethlisberger, Patrik,Roma, Guglielmo,Stiefl, Nikolaus,Uteng, Marianne,Lerchner, Andreas
supporting information, p. 1997 - 2007 (2018/09/14)
CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan–McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX-4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan-CLK inhibition in PMDS.
MONOCYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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Page/Page column 73, (2018/02/28)
Disclosed are compounds of Formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a monocyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
3-(1H-BENZO[D]IMIDAZOL-2-YL)-1H-PYRAZOLO[4,3-B]PYRIDINES AND THERAPEUTIC USES THEREOF
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Paragraph 0650; 0651, (2017/02/28)
4-Azaindazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of a 4-azaindazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
3-(1H-PYRROLO[2,3-C]PYRIDIN-2-YL)-1H-PYRAZOLO[3,4-C]PYRIDINES AND THERAPEUTIC USES THEREOF
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Paragraph 0654; 0655, (2017/02/28)
6-Azaindazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of a 6-azaindazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
3-(1H-INDOL-2-YL)-1H-PYRAZOLO[4,3-B]PYRIDINES AND THERAPEUTIC USES THEREOF
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Paragraph 0659; 0660, (2017/02/28)
4-Azaindazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of a 4-azaindazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
3-(1H-PYRROLO[2,3-B]PYRIDIN-2-YL)-1H-INDAZOLES AND THERAPEUTIC USES THEREOF
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Paragraph 0673; 0674, (2017/02/28)
Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
3-(1H-PYRROLO[3,2-C]PYRIDIN-2-YL)-1H-PYRAZOLO[3,4-B]PYRIDINES AND THERAPEUTIC USES THEREOF
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Paragraph 0654; 0655, (2017/03/08)
7-Azaindazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present disclosure concerns the use of a 7-azaindazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.
