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1H‑Pyrrolo[3,2‑b]pyridine GluN2B-Selective Negative Allosteric Modulators
journal contribution
posted on 2019-01-10, 00:00 authored by Christa C. Chrovian, Akinola Soyode-Johnson, Jessica L. Wall, Jason C. Rech, Jeff Schoellerman, Brian Lord, Kevin J. Coe, Nicholas I. Carruthers, Leslie Nguyen, Xiaohui Jiang, Tatiana Koudriakova, Bartosz Balana, Michael A. LetavicHerein, 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.