Summary:
On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, the new drug was selected as a candidate for further development.
S Conde-Ceide, CM Martínez-Viturro, J Alcázar, PM Garcia-Barrantes, H Lavreysen, C Mackie, PN Vinson, JM Rook, TM Bridges, JS Daniels, A Megens, X Langlois, WH Drinkenburg, A Ahnaou, CM Niswender, CK Jones, GJ Macdonald, T Steckler, PJ Conn, SR Stauffer, JM Bartolomé-Nebreda and CW Lindsley,
ACS medicinal chemistry letters , Jun 2015 11
Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.
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Andrey
February 9, 2016, 7:43pm
2
New research focused on this compound (VU0409551):
DT Balu, Y Li, S Takagi, KT Presti, TS Ramikie, JM Rook, CK Jones, CW Lindsley, PJ Conn, VY Bolshakov and JT Coyle,
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology , 2016 07
There is substantial evidence that NMDA receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia (SCZ). A recent large-scale genome-wide association study identified serine racemase (SR), the enzyme that produces the NMDAR co-agonist D-serine, as a risk gene for SCZ. Serine racemase knockout (SR-/-) mice, which lack D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in SCZ. Metabotropic glutamate receptor 5 (mGlu5)-positive allosteric modulators (PAMs) are currently being developed to treat cognitive dysfunction. We used in vitro electrophysiology to determine whether the mGlu5 PAM VU0409551 directly enhances NMDAR function in hippocampal slices from adult male SR-/- mice. We administered VU0409551 systemically for 5 days to adult male wild-type C57BL/6 animals to determine the optimal dose to test in SR-/- mice. We used western blot analyses and trace-fear conditioning to determine whether 5 days of VU0409551 treatment could reverse the neuroplasticity and learning deficits, respectively, in SR-/- mice. We show that VU0409551 enhances NMDAR function and rescues long-term potentiation in hippocampal slices obtained from SR-/- mice. Systemic treatment with VU0409551 (10 and 30 mg/kg) to wild-type mice causes a dose-dependent increase in the Akt/GS3Kα/β signaling pathway, which is reduced in SR-/- mice and in SCZ. Furthermore, the administration of VU0409551 to SR-/- mice reverses their deficits in several neuroplasticity signaling pathways and improves their contextual fear memory. These results support positive allosteric modulation of mGlu5, particularly with VU0409551, as a viable mechanism to reverse the deficits in NMDAR function, synaptic plasticity, and memory that are known to be impaired in SCZ.
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Interesting. I hope it does well. It will take five years to come to market won’t it? Until then I’m more excited about the once coming out sooner.
Opus
February 9, 2016, 9:50pm
4
It takes allot longer then 5 years from discovery to come out, more like 13 years.
1 Like
Wow. What’s that mean for Iti-007
Opus
February 9, 2016, 11:13pm
6
nothing that drug was discovered along time ago, its in phase 3