Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis.
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.
Malik
Leila
L
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmö, Sweden.
Kelly
Nicholas M
NM
Ma
Jian-Nong
JN
Currier
Erika A
EA
Burstein
Ethan S
ES
Olsson
Roger
R
D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D002417:Cattle; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008253:Macaca mulatta; D008956:Models, Chemical; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry*; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000737:chemistry*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; C480039:MRGPRX2 protein, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C510803:mas-related gene-X1 receptor, human; C054598:corticostatin