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

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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)
Journal	ACS Medicinal Chemistry Letters
DOIs	https://doi.org/10.1021/acsmedchemlett.2c00100
State	Accepted/In press - 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

Access to Document

10.1021/acsmedchemlett.2c00100

Cite this

@article{5dcc99f24c8e42ce962660af2ab445ca,

title = "Synthesis and Biological Characterization of a Series of 2-Sulfonamidebenzamides as Allosteric Modulators of MrgX1",

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.",

keywords = "2-Sulfonamidebenzamide, Mas-related G-protein coupled receptor, MrgX1, Positive allosteric modulator, Structure-activity relationship",

author = "Swagat Sharma and Qi Peng and Vadukoot, {Anish K.} and Aretz, {Christopher D.} and Jensen, {Aaron A.} and Wallick, {Alexander I.} and Xinzhong Dong and Hopkins, {Corey R.}",

note = "Funding Information: This work was generously supported by a grant from the US National Institutes of Health (NIDA: R33DA045303) to C.R.H. Publisher Copyright: {\textcopyright} 2022 American Chemical Society.",

year = "2022",

doi = "10.1021/acsmedchemlett.2c00100",

language = "English (US)",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

}

TY - JOUR

T1 - Synthesis and Biological Characterization of a Series of 2-Sulfonamidebenzamides as Allosteric Modulators of MrgX1

AU - Sharma, Swagat

AU - Peng, Qi

AU - Vadukoot, Anish K.

AU - Aretz, Christopher D.

AU - Jensen, Aaron A.

AU - Wallick, Alexander I.

AU - Dong, Xinzhong

AU - Hopkins, Corey R.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - 2-Sulfonamidebenzamide

KW - Mas-related G-protein coupled receptor

KW - MrgX1

KW - Positive allosteric modulator

KW - Structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=85128598663&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85128598663&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.2c00100

DO - 10.1021/acsmedchemlett.2c00100

M3 - Article

C2 - 35586421

AN - SCOPUS:85128598663

SN - 1948-5875

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this