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

• Published in: Bioorganic & medicinal chemistry 2020-12, Vol.28 (24), p.115818-115818, Article 115818
• Main Authors: Yamaguchi-Sasaki, Toru, Kawaguchi, Takanori, Okada, Atsushi, Tokura, Seiken, Tanaka-Yamamoto, Nozomi, Takeuchi, Tomoki, Ogata, Yuya, Takahashi, Ryo, Kurimoto-Tsuruta, Risa, Tamaoki, Tomokazu, Sugaya, Yutaka, Abe-Kumasaka, Tomoko, Arikawa, Kaho, Yoshida, Ippei, Sugiyama, Hiroyuki, Kanuma, Kosuke, Yoshinaga, Mitsukane
• Format: Article
• Language: English
• Subjects: Atropisomer; Fusion protein; Macrocycle; Pyrazolo[1,5-a]pyrimidines; Respiratory syncytial virus
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115818

[Display omitted] 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.