2022-03-11 Journal Club

J Med Chem. 2022 Feb 24;65(4):3218-3228. doi: 10.1021/acs.jmedchem.1c01709.Epub 2022 Feb 4.

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 Hihara 1Mika Aoki 1Kyoko Yoshizawa 1Tomoki Nishioka 1Shuichi Suzuki 1Shao-Qiu HeQi PengYun GuanXinzhong DongSrinivasa N RajaBarbara S SlusherRana RaisTakashi Tsukamoto

Abstract

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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