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

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

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.

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