Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis

Leila Malik; Nicholas M Kelly; Jian-Nong Ma; Erika A Currier; Ethan S Burstein; Roger Olsson

doi:10.1016/j.bmcl.2009.01.085

Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1729-32. doi: 10.1016/j.bmcl.2009.01.085. Epub 2009 Jan 30.

Authors

Leila Malik¹, Nicholas M Kelly, Jian-Nong Ma, Erika A Currier, Ethan S Burstein, Roger Olsson

Affiliation

¹ ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmö, Sweden.

PMID: 19230660
DOI: 10.1016/j.bmcl.2009.01.085

Abstract

A class of small molecules displaying comparable activities with peptide ligands BAM22 and corticostatin-14 at both the human and rhesus monkey MrgX1 and MrgX2 receptors, respectively, was discovered. A comparative study to compare solid-phase and solution-phase chemistries for the efficient synthesis of the active class, tetracyclic benzimidazoles, was undertaken. The solid-phase chemistry was found to be superior both for the synthesis of analogs and for the synthesis of gram quantities.

MeSH terms

Animals
Benzimidazoles / chemistry
Cattle
Chemistry, Pharmaceutical / methods*
Combinatorial Chemistry Techniques
Drug Design
Humans
Intercellular Signaling Peptides and Proteins
Ligands
Macaca mulatta
Models, Chemical
Nerve Tissue Proteins / agonists*
Nerve Tissue Proteins / chemistry*
Peptides / chemistry
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / chemistry*
Receptors, Neuropeptide / agonists*
Receptors, Neuropeptide / chemistry*
Structure-Activity Relationship

Substances

Benzimidazoles
Intercellular Signaling Peptides and Proteins
Ligands
MRGPRX2 protein, human
Nerve Tissue Proteins
Peptides
Receptors, G-Protein-Coupled
Receptors, Neuropeptide
mas-related gene-X1 receptor, human
corticostatin