Structure-Based Design of Tropane Derivatives as a Novel Series of CCR5 Antagonists with Broad-Spectrum Anti-HIV-1 Activities and Improved Oral Bioavailability

  • J Med Chem. 2022 Dec 22;65(24):16526-16540. doi: 10.1021/acs.jmedchem.2c01383.
Xiong Xie  1  2 ,  Yu-Gui Zheng  3  4  5 ,  Huan Chen  3 ,  Jian Li  1 ,  Rong-Hua Luo  3 ,  Liang Chen  1 ,  Chang-Bo Zheng  4 ,  Shurui Zhang  1  2  6 ,  Panfeng Peng  1 ,  Dakota Ma  1 ,  Liu-Meng Yang  3 ,  Yong-Tang Zheng  3 ,  Hong Liu  1  2 ,  Jiang Wang  1  6
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences /Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
  • 4. School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China.
  • 5. Department of Pharmacy, Guangdong Women and Children Hospital, Guangzhou 511400, China.
  • 6. Lingang Laboratory, Shanghai 200031, China.
PMID: 36472561 DOI: 10.1021/acs.jmedchem.2c01383
Abstract

Blocking the entry of an HIV-1 targeting CCR5 coreceptor has emerged as an attractive strategy to develop HIV therapeutics. Maraviroc is the only CCR5 Antagonist approved by FDA; however, serious side effects limited its clinical use. Herein, 21 novel tropane derivatives (6-26) were designed and synthesized based on the CCR5-maraviroc complex structure. Among them, compounds 25 and 26 had comparable activity to maraviroc and presented more potent inhibitory activity against a series of HIV-1 strains. In addition, compound 26 exhibited synergistic or additive Antiviral effects in combination with Other antiretroviral agents. Compared to maraviroc, both 25 and 26 displayed higher Cmax and AUC0-∞ and improved oral bioavailability in SD rats. In addition, compounds 25 and 26 showed no significant CYP450 inhibition and showed a novel binding mode with CCR5 different from that of maraviroc-CCR5. In summary, compounds 25 and 26 are promising drug candidates for the treatment of HIV-1 Infection.

Products