Synthesis and Biological Characterization of a Series of 2‑Sulfonamidebenzamides as Allosteric Modulators of MrgX1

Swagat Sharma; Qi Peng; Anish K. Vadukoot; Christopher D. Aretz; Aaron A. Jensen; Alexander I. Wallick; Xinzhong Dong; Corey R. Hopkins

doi:10.1021/acsmedchemlett.2c00100

Synthesis and Biological Characterization of a Series of 2‑Sulfonamidebenzamides as Allosteric Modulators of MrgX1

Swagat Sharma, Qi Peng, Anish K. Vadukoot, Christopher D. Aretz, Aaron A. Jensen, Alexander I. Wallick, Xinzhong Dong, Corey R. Hopkins

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Abstract

The present study describes our continued efforts in the discovery and characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1. MrgX1 has been shown to be an attractive target as a nonopioid receptor for the potential treatment of chronic pain. Working from our original compound ML382 and utilizing iterative medicinal chemistry, we have identified key halogen substituents that improve MrgX1 potency by ∼8-fold. In addition, we have evaluated the compounds in Tier 1 drug metabolism and pharmacokinetics assays and have identified key compounds that impart improved potency and microsomal stability.

Original language	English (US)
Pages (from-to)	841-847
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00100
State	Published - May 12 2022

Keywords

2-Sulfonamidebenzamide
Mas-related G-protein coupled receptor
MrgX1
Positive allosteric modulator
Structure−activity relationship

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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abstract = "The present study describes our continued efforts in the discovery and characterization of a series of 2-sulfonamidebenzamides as allosteric modulators of MrgX1. MrgX1 has been shown to be an attractive target as a nonopioid receptor for the potential treatment of chronic pain. Working from our original compound ML382 and utilizing iterative medicinal chemistry, we have identified key halogen substituents that improve MrgX1 potency by ∼8-fold. In addition, we have evaluated the compounds in Tier 1 drug metabolism and pharmacokinetics assays and have identified key compounds that impart improved potency and microsomal stability.",

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AU - Vadukoot, Anish K.

AU - Aretz, Christopher D.

AU - Jensen, Aaron A.

AU - Wallick, Alexander I.

AU - Dong, Xinzhong

AU - Hopkins, Corey R.

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KW - Positive allosteric modulator

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Synthesis and Biological Characterization of a Series of 2‑Sulfonamidebenzamides as Allosteric Modulators of MrgX1

Abstract

Keywords

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