Abstract
Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
| Original language | English |
|---|---|
| Pages (from-to) | 925-930 |
| Number of pages | 6 |
| Journal | ACS Medicinal Chemistry Letters |
| Volume | 8 |
| Issue number | 9 |
| DOIs | |
| State | Published - 1 Jan 2017 |
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Keywords
- Negative allosteric modulator (NAM)
- VU6010572
- depression
- metabotropic glutamate receptor 3 (mGlu)
- physiochemical properties
Cite this
}
Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs. / Engers, Julie L.; Bollinger, Katrina A.; Weiner, Rebecca L.; Rodriguez, Alice L.; Long, Madeline F.; Breiner, Megan M.; Chang, Sichen; Bollinger, Sean R.; Bubser, Michael; Jones, Carrie K.; Morrison, Ryan D.; Bridges, Thomas M.; Blobaum, Anna L.; Niswender, Colleen M.; Conn, P. Jeffrey; Emmitte, Kyle Allen; Lindsley, Craig W.
In: ACS Medicinal Chemistry Letters, Vol. 8, No. 9, 01.01.2017, p. 925-930.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs
AU - Engers, Julie L.
AU - Bollinger, Katrina A.
AU - Weiner, Rebecca L.
AU - Rodriguez, Alice L.
AU - Long, Madeline F.
AU - Breiner, Megan M.
AU - Chang, Sichen
AU - Bollinger, Sean R.
AU - Bubser, Michael
AU - Jones, Carrie K.
AU - Morrison, Ryan D.
AU - Bridges, Thomas M.
AU - Blobaum, Anna L.
AU - Niswender, Colleen M.
AU - Conn, P. Jeffrey
AU - Emmitte, Kyle Allen
AU - Lindsley, Craig W.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
AB - Herein, we detail the optimization of the mGlu3 NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu3 NAM scaffold that engenders potent and selective mGlu3 inhibition (mGlu3 IC50 = 245 nM, mGlu2 IC50 > 30 μM) with excellent central nervous system penetration (rat brain/plasma Kp = 1.2, Kp,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).
KW - Negative allosteric modulator (NAM)
KW - VU6010572
KW - depression
KW - metabotropic glutamate receptor 3 (mGlu)
KW - physiochemical properties
UR - http://www.scopus.com/inward/record.url?scp=85029519189&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.7b00249
DO - 10.1021/acsmedchemlett.7b00249
M3 - Article
VL - 8
SP - 925
EP - 930
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 9
ER -