2. Academic Validation
  3. Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors

Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors

  • J Med Chem. 2018 Oct 25;61(20):9177-9204. doi: 10.1021/acs.jmedchem.8b00819.
Daqiang Li 1,  Xiaotuan Zhang 2 3,  Xiaodong Ma 4,  Lei Xu 2 5 3,  Jianjun Yu 1,  Lixin Gao 2,  Xiaobei Hu 2,  Jiankang Zhang 6,  Xiaowu Dong 1,  Jia Li 2,  Tao Liu 1,  Yubo Zhou 2,  Yongzhou Hu 1
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research , College of Pharmaceutical Sciences, Zhejiang University , Hangzhou , 310058 , People's Republic of China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
  • 3 Graduate School , University of Chinese Academy of Sciences , No. 19A Yuquan Road , 100049 Beijing , China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy , Anhui University of Chinese Medicine , Hefei 230031 , China.
  • 5 School of Life Science and Technology , ShanghaiTech University , Shanghai , 201203 , China.
  • 6 Zhejiang University City College , Hangzhou 310015 , Zhejiang China.
PMID: 30265557 DOI: 10.1021/acs.jmedchem.8b00819
Abstract

Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available Proteasome inhibitors, 30 oprozomib-derived macrocyclic Peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure-activity relationship (SAR) studies. As a consequence, the macrocyclic Peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo Proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, β5) inhibitory potency (IC50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.

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