Design, synthesis, and optimization of a series of 2-azaspiro[3.3]heptane derivatives as orally bioavailable fetal hemoglobin inducers

  • Bioorg Med Chem Lett. 2020 Oct 1;30(19):127425. doi: 10.1016/j.bmcl.2020.127425.
Katsushi Katayama  1 ,  Tomoyuki Tsunemi  2 ,  Kazuo Miyazaki  2 ,  Kouichi Uoto  2 ,  Ryosuke Yoshioka  2 ,  Hideki Terashima  2 ,  Maki Terakawa  2 ,  Kyoko Yamashiro  2 ,  Munetada Haruyama  2 ,  Hiroaki Maeda  2 ,  Tomohiro Makino  2
Affiliations
  • 1. Asubio Pharma Co. Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan. Electronic address: [email protected].
  • 2. Asubio Pharma Co. Ltd, 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
PMID: 32717372 DOI: 10.1016/j.bmcl.2020.127425
Abstract

Pharmacological reactivation of the γ-globin gene for the production of fetal Hemoglobin (HbF) is a promising approach for the management of β-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure-activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of β-hemoglobinopathies, including SCD.

Keywords
Fetal hemoglobin; Globin switching; Sickle cell disease (SCD); Structure–activity relationship (SAR); β-Thalassemia; γ-Globin.
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