868280-61-9

Upstream product

• 66739-89-7 4-(1,3-dioxolan-2-yl)benzonitrile 
• 90878-19-6 phenethylmagnesium chloride 
• 100-39-0 benzyl bromide 
• 105-07-7 4-cyanobenzaldehyde 
• 6921-34-2 benzylmagnesium chloride 

Downstream Products

• 893423-65-9 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-methoxy-3-phenyl-1,6-naphthyridine 
• 917363-82-7 5-chloro-2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridine 
• 345958-23-8 4-(2-phenylacetyl)benzaldehyde 
• 1240308-54-6 1-(4-phenethylbenzyl)azetidine-3-carboxylic acid 
• 1240308-53-5 1-(4-(2-phenylacetyl)benzyl)azetidine-3-carboxylic acid 
• 893422-47-4 3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-1,6-naphthyridin-5(6H)-one 
• 917363-87-2 4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde 
• 917363-89-4 4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde 
• 917363-93-0 [4-(3-methyl-9-phenyl-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-8-yl)-benzyl]-carbamic acid tert-butyl ester 

Relevant academic research and scientific papers

Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt

The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders

S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.

AGONISTS AND ANTAGONISTS OF THE S1P5 RECEPTOR, AND METHODS OF USES THEREOF

Disclosed are compounds that are agonists or antagonists of the S1P5 receptor, compositions comprising said compounds, and methods of using said compounds and compositions. In certain embodiments, said compounds are 1-benzylazetidine-3-carboxylic acid derivatives. In certain embodiments, said methods relate to the treatment of neuropatic pain and/or a neurodegenerative disorder. In certain embodiments, said compounds may be used in combination with a second therapeutic agent.

Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecu

INHIBITORS OF AKT ACTIVITY

The present invention is directed to compounds which contain substituted naphthyridines which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention. These substituted naphthyridines have unexpected advantageous properties when compared to other naphthyridines reported in PCT publication WO2003/086394, such unexpected advantageous properties may include increased cellular potency/solubility, greater selectivity, enhanced pharmacokinetic properties, lack of off target activity and so on.

INHIBITORS OF AKT ACTIVITY

The instant invention provides for compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and method

INHIBITORS OF AKT ACTIVITY

The instant invention provides for substituted naphthyridine compounds that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.

INHIBITORS OF AKT ACTIVITY

The present invention is directed to compounds which contain substituted pyridazines and pyrimidines moieties which inhibit the activity of Akt, a serine/threonine protein kinase. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for treating cancer comprising administration of the compounds of the invention.