TY - JOUR
T1 - Thieno[2,3-d]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1)
AU - Berhane, Ilyas
AU - Hin, Niyada
AU - Thomas, Ajit G.
AU - Huang, Qian
AU - Zhang, Chi
AU - Veeravalli, Vijayabhaskar
AU - Wu, Ying
AU - Ng, Justin
AU - Alt, Jesse
AU - Rojas, Camilo
AU - Hihara, Hiroe
AU - Aoki, Mika
AU - Yoshizawa, Kyoko
AU - Nishioka, Tomoki
AU - Suzuki, Shuichi
AU - He, Shao Qiu
AU - Peng, Qi
AU - Guan, Yun
AU - Dong, Xinzhong
AU - Raja, Srinivasa N.
AU - Slusher, Barbara S.
AU - Rais, Rana
AU - Tsukamoto, Takashi
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/2/24
Y1 - 2022/2/24
N2 - Mas-related G protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and potential target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 have the potential to preferentially activate the receptors at the central terminals of primary sensory neurons and minimize itch side effects caused by peripheral activation. Using a high-throughput screening (HTS) hit, a series of thieno[2,3-d]pyrimidine-based molecules were synthesized and evaluated as human MRGPRX1 PAMs in HEK293 cells stably transfected with human MrgprX1 gene. An iterative process to improve potency and metabolic stability led to the discovery of orally available 6-(tert-butyl)-5-(3,4-dichlorophenyl)-4-(2-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine (1t), which can be distributed to the spinal cord, the presumed site of action, following oral administration. In a neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI), compound 1t (100 mg/kg, po) reduced behavioral heat hypersensitivity in humanized MRGPRX1 mice, demonstrating the therapeutic potential of MRGPRX1 PAMs in treating neuropathic pain.
AB - Mas-related G protein-coupled receptor X1 (MRGPRX1) is a human sensory neuron-specific receptor and potential target for the treatment of pain. Positive allosteric modulators (PAMs) of MRGPRX1 have the potential to preferentially activate the receptors at the central terminals of primary sensory neurons and minimize itch side effects caused by peripheral activation. Using a high-throughput screening (HTS) hit, a series of thieno[2,3-d]pyrimidine-based molecules were synthesized and evaluated as human MRGPRX1 PAMs in HEK293 cells stably transfected with human MrgprX1 gene. An iterative process to improve potency and metabolic stability led to the discovery of orally available 6-(tert-butyl)-5-(3,4-dichlorophenyl)-4-(2-(trifluoromethoxy)phenoxy)thieno[2,3-d]pyrimidine (1t), which can be distributed to the spinal cord, the presumed site of action, following oral administration. In a neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI), compound 1t (100 mg/kg, po) reduced behavioral heat hypersensitivity in humanized MRGPRX1 mice, demonstrating the therapeutic potential of MRGPRX1 PAMs in treating neuropathic pain.
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U2 - 10.1021/acs.jmedchem.1c01709
DO - 10.1021/acs.jmedchem.1c01709
M3 - Article
C2 - 35119273
AN - SCOPUS:85124897072
SN - 0022-2623
VL - 65
SP - 3218
EP - 3228
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 4
ER -