TY - JOUR
T1 - Discovery of Benzamidine- And 1-Aminoisoquinoline-Based Human MAS-Related G-Protein-Coupled Receptor X1 (MRGPRX1) Agonists
AU - Prchalová, Eva
AU - Hin, Niyada
AU - Thomas, Ajit G.
AU - Veeravalli, Vijayabhaskar
AU - Ng, Justin
AU - Alt, Jesse
AU - Rais, Rana
AU - Rojas, Camilo
AU - Li, Zhe
AU - Hihara, Hiroe
AU - Aoki, Mika
AU - Yoshizawa, Kyoko
AU - Nishioka, Tomoki
AU - Suzuki, Shuichi
AU - Kopajtic, Theresa
AU - Chatrath, Sheena
AU - Liu, Qin
AU - Dong, Xinzhong
AU - Slusher, Barbara S.
AU - Tsukamoto, Takashi
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072686778&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072686778&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b01003
DO - 10.1021/acs.jmedchem.9b01003
M3 - Article
C2 - 31498617
AN - SCOPUS:85072686778
SN - 0022-2623
VL - 62
SP - 8631
EP - 8641
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 18
ER -