1H‑Pyrrolo[3,2‑b]pyridine GluN2B-Selective Negative Allosteric Modulators
Version 2 2019-01-10, 20:43
Version 1 2019-01-10, 20:37
Posted on 2019-01-10 - 20:43
Herein, we disclose a series of selective
GluN2B negative allosteric
modulators containing a 1H-pyrrolo[3,2-b]pyridine core. Lead optimization efforts included increasing brain
penetration as well as decreasing cytochrome P450 inhibition and hERG
channel binding. The series was also optimized to reduce metabolic
turnover in human and rat. Compounds 9, 25, 30, and 34 have good in vitro GluN2B
potency and good predicted absorption, but moderate to high projected
clearance. They were assessed in vivo to determine their target engagement.
All four compounds achieved >75% receptor occupancy after an oral
dose of 10 mg/kg in rat. Compound 9 receptor occupancy
was measured in a dose–response experiment, and its ED50 was found to be 2.0 mg/kg.
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Chrovian, Christa C.; Soyode-Johnson, Akinola; Wall, Jessica L.; Rech, Jason C.; Schoellerman, Jeff; Lord, Brian; et al. (2019). 1H‑Pyrrolo[3,2‑b]pyridine GluN2B-Selective Negative Allosteric Modulators. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.8b00542
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AUTHORS (13)
CC
Christa C. Chrovian
AS
Akinola Soyode-Johnson
JW
Jessica L. Wall
JR
Jason C. Rech
JS
Jeff Schoellerman
BL
Brian Lord
KC
Kevin J. Coe
NC
Nicholas I. Carruthers
LN
Leslie Nguyen
XJ
Xiaohui Jiang
TK
Tatiana Koudriakova
BB
Bartosz Balana
ML
Michael A. Letavic