Discovery of Benzamidine- and 1‑Aminoisoquinoline-Based Human MAS-Related G‑Protein-Coupled Receptor X1 (MRGPRX1) Agonists

Mas-related
G-protein-coupled receptor X1 (MRGPRX1) is a human
sensory neuron-specific receptor and has been actively investigated
as a therapeutic target for the treatment of pain. By use of two HTS
screening hit compounds, 4-(4-(benzyloxy)-3-methoxybenzylamino)­benzimidamide
(5a) and 4-(2-(butylsulfonamido)-4-methylphenoxy)­benzimidamide
(11a), as molecular templates, a series of human MRGPRX1
agonists were synthesized and evaluated for their agonist activity
using HEK293 cells stably transfected with human MrgprX1. Conversion
of the benzamidine moiety into a 1-aminoisoquinoline moiety carried
out in the later stage of structural optimization led to the discovery
of a highly potent MRGPRX1 agonist, N-(2-(1-aminoisoquinolin-6-yloxy)-4-methylphenyl)-2-methoxybenzene­sulfonamide
(16), not only devoid of positively charged amidinium
group but also with superior selectivity over opioid receptors. In
mice, compound 16 displayed favorable distribution to
the spinal cord, the presumed site of action for the MRGPRX1-mediated
analgesic effects.