2. Academic Validation
  3. Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide

Study on chemical modification and analgesic activity of N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide

  • Eur J Med Chem. 2020 May 15:194:112236. doi: 10.1016/j.ejmech.2020.112236.
Cunbin Nie 1,  Qifei Li 2,  Yue Qiao 1,  Jing Hu 1,  Mengkang Gao 1,  Yusui Wang 1,  Zhenrui Qiao 1,  Qiang Wang 3,  Lin Yan 4,  Hai Qian 5
Affiliations

Affiliations

  • 1 Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China.
  • 2 State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China.
  • 3 School of Pharmaceutical Sciences, South-Central University for Nationalities, 182 Minyuan Road, Wuhan, Hubei, 430074, China.
  • 4 Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China. Electronic address: yanlin@henu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China. Electronic address: qianhai24@163.com.
PMID: 32217416 DOI: 10.1016/j.ejmech.2020.112236
Abstract

N-(4-Tert-butylphenyl)-4-(3-chloropyridin-2-yl) piperazine-1-carboxamide (BCTC) is a potent and extensively studied urea-based TRPV1 antagonist. Although BCTC was effective in alleviating chronic pain in rats, it showed obvious hyperthermia side-effect and unsatisfactory pharmacokinetic profile, therefore, it was not developed further. In order to enrich the structural types of urea-based TRPV1 antagonists, two series of novel analogs, in which the pyridine ring of BCTC was replaced with a mildly basic pyrimidine ring or 1,2,3,4-tetrahydro-β-carboline scaffold, were designed and synthesized. Advancing the structure-activity relationship of these two series led to the discovery of N-(4-methoxyphenyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxamide (7o), with an improved pharmacological and tolerability profile compared with the lead compound BCTC.

Keywords

BCTC; Hyperthermia; Pyrimidine; Tetrahydro-β-carboline; Transient receptor potential vanilloid type 1.

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