Thieno[2,3- d ]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1).
Ilyas BerhaneNiyada HinAjit G ThomasQian HuangChi ZhangVijayabhaskar VeeravalliYing WuJustin NgJesse AltCamilo RojasHiroe HiharaMika AokiKyoko YoshizawaTomoki NishiokaShuichi SuzukiShao-Qiu HeQi PengYun GuanXinzhong DongSrinivasa N RajaBarbara S SlusherRana RaisTakashi TsukamotoPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- magnetic resonance imaging
- neuropathic pain
- spinal cord
- spinal cord injury
- endothelial cells
- small molecule
- induced pluripotent stem cells
- cell proliferation
- magnetic resonance
- type diabetes
- induced apoptosis
- risk assessment
- adipose tissue
- signaling pathway
- transcription factor
- endoplasmic reticulum stress
- insulin resistance
- monoclonal antibody
- high fat diet induced