2. Academic Validation
  3. Synthesis and biological evaluation of methylpyrimidine-fused tricyclic diterpene analogs as novel oral anti-late-onset hypogonadism agents

Synthesis and biological evaluation of methylpyrimidine-fused tricyclic diterpene analogs as novel oral anti-late-onset hypogonadism agents

  • Eur J Med Chem. 2019 Aug 15;176:21-40. doi: 10.1016/j.ejmech.2019.05.005.
Jie Bai 1,  Jia Xie 2,  Yajing Xing 2,  Li-Ting Wang 1,  Jiuqing Xie 2,  Fan Yang 1,  Ting Liu 1,  Mingyao Liu 2,  Jie Tang 1,  Zhengfang Yi 2,  Wen-Wei Qiu 3
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
PMID: 31091478 DOI: 10.1016/j.ejmech.2019.05.005
Abstract

Male late-onset hypogonadism (LOH) is reported as one of the most common age-related diseases occurred in middle-aging men. Testosterone replacement therapy (TRT) is currently the main clinical treatment for LOH, however it has obvious side effects. A 2-methylpyrimidine-fused tricyclic diterpene analog 7 was afforded as anti-LOH hit, which was screened out from our small synthetic library. Then a series of derivates were designed and synthesized based on the hit and their effects in promoting testosterone production and cytotoxicities were evaluated in mouse TM3 Leydig cells. The most potent and safe compound 29 (SH379) was obtained, which significantly promoted the expression of the key testosterone synthesis-related Enzymes StAR and 3β-HSD. Further studies discovered that 29 could stimulate Autophagy through regulating AMPK/mTOR signaling pathway. More importantly, 29 increased the testosterone levels and the sperm viability and motility in PADAM (partial androgen deficiency in aging males) rats obviously and displayed almost no side effects. Furthermore, Preliminary pharmacokinetics evaluation also indicated an excellent oral bioavailability of 29. Therefore, these methylpyrimidine-fused tricyclic diterpene analogs could be used as leads for the development of a new type of potential anti-LOH agent.

Keywords

Late-onset hypogonadism; Testosterone synthesis; Tricyclic diterpene.

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