2. Academic Validation
  3. Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity

Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity

  • ACS Med Chem Lett. 2021 Mar 5;12(4):572-578. doi: 10.1021/acsmedchemlett.0c00571.
Sicheng Zhang 1,  Luis O Romero 2 3,  Shanshan Deng 1,  Jiaxing Wang 1,  Yong Li 4,  Lei Yang 4,  David J Hamilton 5,  Duane D Miller 1,  Francesca-Fang Liao 6,  Julio F Cordero-Morales 2,  Zhongzhi Wu 1,  Wei Li 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 2 Department of Physiology, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 3 Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences, Memphis, Tennessee 38163, United States.
  • 4 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 5 Department of Comparative Medicine, College of Graduate Health Sciences, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 6 Department of Pharmacology, Addiction Science, and Toxicology, the University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
PMID: 33859797 DOI: 10.1021/acsmedchemlett.0c00571
Abstract

The overactivation of transient receptor potential canonical 3 (TRPC3) is associated with neurodegenerative diseases and hypertension. Pyrazole 3 (Pyr3) is reported as the most selective TRPC3 inhibitor, but it has two inherent structural limitations: (1) the labile ester moiety leads to its rapid hydrolysis to the inactive Pyr8 in vivo, and (2) the alkylating trichloroacrylic amide moiety is known to be toxic. To circumvent these limitations, we designed a series of conformationally restricted Pyr3 analogues and reported that compound 20 maintains high potency and selectivity for human TRPC3 over its closely related TRP channels. It has significantly improved metabolic stability compared with Pyr3 and has a good safety profile. Preliminary evaluation of 20 demonstrated its ability to rescue Aβ-induced neuron damage with similar potency to that of Pyr3 in vitro. Collectively, these results suggest that 20 represents a promising scaffold to potentially ameliorate the symptoms associated with TRPC3-mediated neurological and cardiovascular disorders.

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