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. 2015 Jul 20;6(9):1015-8.
doi: 10.1021/acsmedchemlett.5b00247. eCollection 2015 Sep 10.

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

Curt A Dvorak  1 , Heather Coate  1 , Diane Nepomuceno  1 , Michelle Wennerholm  1 , Chester Kuei  1 , Brian Lord  1 , David Woody  1 , Pascal Bonaventure  1 , Changlu Liu  1 , Timothy Lovenberg  1 , Nicholas I Carruthers  1
Affiliations

Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor

Curt A Dvorak et al. ACS Med Chem Lett. .

Abstract

A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure-activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood-brain barrier and have good drug-like properties amenable for oral dosing in rat.

Keywords: GPR139; Orphan receptors; agonists; glycine amides.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure of GPR139 agonists.
Scheme 1
Scheme 1. High Throughput Screening Lead and Initial Optimization
Scheme 2
Scheme 2. Synthesis of Compounds 7–9
Reagents and conditions: (a) Boc-Gly-OH, EDCI, HOBt, iPr2NEt, DCM; (b) 4 M HCl, dioxane; (c) R1ArCOCl, Et3N, DCM; (d) Boc-NHCH2CHO, NaBH(OAc)3, DCM; (e) 4 M HCl, dioxane; (f) 3-chlorobenzoyl chloride, Et3N, DCM; (g) 3-chlorobenzaldehyde, NaBH(OAc)3, DCM.
Figure 2
Figure 2
Total and non-specific binding of [3H]-7c.
See this image and copyright information in PMC

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