2. Academic Validation
  3. Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties

Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties

  • Bioorg Med Chem. 2020 Dec 15;28(24):115818. doi: 10.1016/j.bmc.2020.115818.
Toru Yamaguchi-Sasaki 1,  Takanori Kawaguchi 1,  Atsushi Okada 2,  Seiken Tokura 2,  Nozomi Tanaka-Yamamoto 1,  Tomoki Takeuchi 1,  Yuya Ogata 1,  Ryo Takahashi 1,  Risa Kurimoto-Tsuruta 1,  Tomokazu Tamaoki 1,  Yutaka Sugaya 3,  Tomoko Abe-Kumasaka 3,  Kaho Arikawa 3,  Ippei Yoshida 3,  Hiroyuki Sugiyama 3,  Kosuke Kanuma 1,  Mitsukane Yoshinaga 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 2 Discovery Technologies Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 3 Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
PMID: 33190073 DOI: 10.1016/j.bmc.2020.115818
Abstract

The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.

Keywords

Atropisomer; Fusion protein; Macrocycle; Pyrazolo[1,5-a]pyrimidines; Respiratory syncytial virus.

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