PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Preparation of N‑Phenyl-lactam Derivatives Capable of Stimulating Neurogenesis and Their Use in the Treatment of Neurological Disorders Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States Preparation of N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological
Title:
disorders Patent/Patent Application Number: WO2015107053A1
Publication date:
July 23rd, 2015
Priority date:
January 20th, 2014
Priority Application:
EP14151754.0
Inventors: Assignee Company:
Jakob-Roetne, R.; Wichmann, J.; Peters, J. U.; Jagasia, R. Hoffmann La Roche AG
Disease Area:
Central Nervous System
Summary:
Neurogenesis, the process of generating new, functional neurons from neural stem cells, occurs in two neurogenic regions
Biological Target:
Neurodegenerative and neuropsychiatric diseases
of the brain. The first region is the subgranular zone (SGZ) in the dentate gyrus of the hippocampus. New dentate granular cells are generated in this area. In the second area of neurogenesis, the subventricular zone (SVZ) of the lateral ventricles, new neural stem cells are converted to functional neurons that migrate through the rostral migratory system (RMS) to the olfactory bulb. Neurogenesis is very limited in other regions of the brain but may be induced after brain injury (e.g., stroke). It has been suggested that adult neurogenesis plays a role in cognition and emotional states. Further, the disruption of normal neurogenesis may be a contributing factor in the progression of a range of neurodegenerative diseases and psychiatric disorders. Decreased adult neurogenesis has been linked to chronic stress, depression, sleep deprivation, and aging. Antidepressants, however, promote adult neurogenesis. As a result of these and other related observation, it has been suggested that compounds capable of stimulating adult neurogenesis could be useful as therapeutic agents for a number of important neurodegenerative conditions and neuropsychiatric diseases. These include schizophrenia, obsessive compulsive personality disorder, major depression, bipolar disorder, anxiety disorders, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson’s disease, dementia, Alzheimer’s disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction (00 chemobrain00 ), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, stroke, and disturbances due to radiation therapy, chronic stress, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine. The present disclosure describes compounds capable of stimulating neurogenesis and their use as therapeutic agents for the aforementioned conditions. Important Compound Classes:
Definitions:
Het is oxazole-5-yl, pyridin-4-yl, or pyrazol-4-yl; R1/R2 are, independently from each other, hydrogen, lower alkyl, lower alkoxy, or halogen; W is CH2 or CH2CH2; X is CR3R4 or NR5; R3 is hydrogen or lower alkyl; R4 is (CH2)nphenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or lower alkyl; R5 is CHR-phenyl or CH2CHR-phenyl, optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or lower alkyl, or is CHR-pyridin-2-, -3-, or 4-yl; R is hydrogen or lower alkyl; n is 0 or 1.
Received: September 5, 2015 Published: October 05, 2015 r 2015 American Chemical Society
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dx.doi.org/10.1021/acsmedchemlett.5b00355 | ACS Med. Chem. Lett. 2015, 6, 1092–1094
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Key Structures:
Recent Review Articles:
Lindvall, O.; Kokaia, Z. Stem cells in human neurodegenerative disorders - time for clinical translation? J. Clin. Invest. 2010, 120 (1), 2940. Hong, H. S.; Kim, D. Y.; Yoon, K. J.; Son, Y. A new paradigm for stem cell therapy: Substance-P as a stem cell-stimulating agent. Arch. Pharm. Res. 2011, 34 (12), 20032006. Ding, Y. X.; Wei, L. C.; Wang, Y. Z.; Cao, R.; Wang, X.; Chen, L. W. Molecular manipulation targeting regulation of dopaminergic differentiation and proliferation of neural stem cells or pluripotent stem cells. CNS Neurol. Disorders Drug Targets 2011, 10 (4), 51728.
Biological Assay:
Neural Stem Cell Proliferation Assay: Neurogenic properties of small molecules are determined based on the proliferation of human embryonic stem cell derived neural stem cells (NSCs), which were derived via a dual smad inhibition. Compound response is measured by the increase in cells based on ATP levels (Promega:CellTiterGlo) after an incubation period of 4 days. NSCs are thawed and expanded over three passages. On the 14th day, NSCs are seeded in Polyornithin/Laminin coated 384-well plates at a cell density of 21,000 cells/cm2 in a media volume of 38 μL. Four hours after cell seeding, compound solutions are added at a volume of 2 μL. Stock solutions of the compounds (water, 5% DMSO) are diluted to obtain a dose response (11 points, dilution factor is 2), ranging from 8 μM to 8 nM. Controls are run to consistently determine the neurogenic properties of the cells. Negative (neutral) control is cell culture media (final DMSO concentration: 0.25%). Positive controls are 1. Cell culture media + 100 ng/mL FGF2 (final DMSO concentration: 0.1%). 2. Cell culture media + 20 ng/mL EGF (final DMSO concentration: 0.1%). 3. Cell culture media + 100 ng/mL Wnt3a (final DMSO concentration: 0.1%). After 4 days of incubation at 37 °C, 5% CO2, the amount of ATP per well is quantified. The ATP concentration is proportional to the cell number. ATP is quantified by using the Promega CellTiterGlo kit. The CellTiterGlo reagents contain a cell lysis buffer, thermostable luciferase (UltraGloTM recombinant luciferase), magnesium, and luciferin. Luciferin reacts with ATP producing oxyluciferin, AMP, and light. The luminescence signal is proportional to the ATP content. The value of negative (neutral) control is determined for each assay plate by taking the average of 16 negative control wells. The neurogenic compound response is calculated for each compound as (compound/negative control) 100. The values of EC150 from the dose response curve are determined for each test compound. The EC150 is the compound concentration at which 150% activity of control (100%) is reached.
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dx.doi.org/10.1021/acsmedchemlett.5b00355 |ACS Med. Chem. Lett. 2015, 6, 1092–1094
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Biological Data:
Claims:
16 Claims 10 Composition of matter claims 5 Method of use claims 1 Process claim
’ AUTHOR INFORMATION Corresponding Author
*Tel: 215-707-1085. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/acsmedchemlett.5b00355 |ACS Med. Chem. Lett. 2015, 6, 1092–1094
