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

Abstract

Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1Hpyrrolo[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 ED 50 was found to be 2.0 mg/kg.

Design, Synthesis, and Preclinical Evaluation of 3-Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders

“… a IC 50 values were determined by a calcium mobilization assay in inducible CHO T-Rex cells heterologously expressing the hGluN1a/GluN2B receptor. Values reported are the mean ± SD of at least three experiments unless otherwise stated. b K i values were determined using a radioligand competitive binding assay in rat cortex membranes using 3-[ 3 H] 1-(azetidin-1-yl)-2-[6-(4-fluoro-3-methyl-phenyl)­pyrrolo­[3,2- b ]­pyridin-1-yl]­ethanone . Values reported are the mean ± SD of at least three experiments unless otherwise stated. c Kinetic solubility in aqueous buffer. d Stability in human and rat liver microsomes.…”

“… b K i values were determined using a radioligand competitive binding assay in rat cortex membranes using 3-[ 3 H] 1-(azetidin-1-yl)-2-[6-(4-fluoro-3-methyl-phenyl)­pyrrolo­[3,2- b ]­pyridin-1-yl]­ethanone . Values reported are the mean ± SD of at least three experiments unless otherwise stated. …”

“…A strategy to lower efflux ratios emerged at around this point in the SAR, when concurrent work on a second series of GluN2B NAMs containing a 1 H -pyrrolo­[3,2- b ]­pyridine core indicated that somewhat lower efflux ratios were measured for many of the examples had thiophenes on the LHS as phenyl bioisosteres . An example from that report in which 4-fluoro-3-methylphenyl was applied to the 1 H -pyrrolo­[3,2- b ]­pyridine core LHS ( 8 , Figure ) had an efflux ratio of 5.4 and a plasma C max of 1380 ng/mL in rat, whereas the comparator molecule with a 5-(trifluoromethyl)­thiophen-2-yl group in the place of 4-fluoro-3-methylphenyl ( 9 ) had an efflux ratio of 3.5 and a higher C max of 2330 ng/mL in rat (Figure ).…”

“…The dose dependency of 12 was obtained from GluN2B rat hippocampal occupancy measurements after oral administration at 8 different doses (Figure ). Receptor occupancy was determined at 60 min post dose (3 animals per group), by ex vivo ARG . The calculations were made versus naïve control as described for the 6 h time course ( vide supra ).…”

“… a K i values were determined using a radioligand competitive binding assay in rat cortex membranes using ([ 3 H]-1-(azetidin-1-yl)-2-(6-(4-fluoro-3-methylphenyl)-1 H -pyrrolo­[3,2- b ]­pyridin-1-yl)­ethanone . Values reported are the mean of three experiments ± SD, unless otherwise stated. b K i measured in cortical neurons. c IC 50 values are reported in nM and were determined by a calcium mobilization assay in inducible CHO T-Rex cells heterologously expressing the hGluN1a/GluN2A, hGluN1a/GluN2C, or hGluN1a/GluN2D receptor. d Stability in human and rat liver microsomes.…”