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. 2019 Jan 10;10(3):261-266.
doi: 10.1021/acsmedchemlett.8b00542. eCollection 2019 Mar 14.

1 H-Pyrrolo[3,2- b]pyridine GluN2B-Selective Negative Allosteric Modulators

Christa C Chrovian  1 , Akinola Soyode-Johnson  1 , Jessica L Wall  1 , Jason C Rech  1 , Jeff Schoellerman  1 , Brian Lord  1 , Kevin J Coe  1 , Nicholas I Carruthers  1 , Leslie Nguyen  1 , Xiaohui Jiang  1 , Tatiana Koudriakova  1 , Bartosz Balana  1 , Michael A Letavic  1
Affiliations

1 H-Pyrrolo[3,2- b]pyridine GluN2B-Selective Negative Allosteric Modulators

Christa C Chrovian et al. ACS Med Chem Lett. .

Abstract

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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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Chart 1
Chart 1. GluN2B-Selective NAMs Assessed in Clinical Proof of Concept Trials for Depression
Figure 1
Figure 1
HTS hits and initial core optimization of fused pyridines.
Figure 2
Figure 2
Dose versus receptor occupancy at 0.5 h in rat in a dose–response experiment of 9.
See this image and copyright information in PMC

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