Thieno[2,3-d]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1)

Ilyas Berhane, Niyada Hin, Ajit G. Thomas, Qian Huang, Chi Zhang, Vijayabhaskar Veeravalli, Ying Wu, Justin Ng, Jesse Alt, Camilo Rojas, Hiroe Hihara, Mika Aoki, Kyoko Yoshizawa, Tomoki Nishioka, Shuichi Suzuki, Shao Qiu He, Qi Peng, Yun Guan, Xinzhong Dong, Srinivasa N. RajaBarbara S. Slusher, Rana Rais, Takashi Tsukamoto

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3218-3228
Number of pages11
JournalJournal of medicinal chemistry
Volume65
Issue number4
DOIs
StatePublished - Feb 24 2022

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine

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