2. Academic Validation
  3. Optimization and in vivo evaluation of pyrazolopyridines as a potent and selective PI3Kδ inhibitor

Optimization and in vivo evaluation of pyrazolopyridines as a potent and selective PI3Kδ inhibitor

  • Bioorg Med Chem. 2018 Aug 7;26(14):3917-3924. doi: 10.1016/j.bmc.2018.06.012.
Toshihiro Hamajima 1,  Fumie Takahashi 2,  Koji Kato 2,  Yukihito Sugano 2,  Susumu Yamaki 2,  Ayako Moritomo 2,  Satoshi Kubo 2,  Koji Nakamura 2,  Kaoru Yamagami 2,  Nozomu Hamakawa 2,  Koji Yokoo 2,  Hidehiko Fukahori 2
Affiliations

Affiliations

  • 1 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: toshihiro.hamajima@astellas.com.
  • 2 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
PMID: 29907471 DOI: 10.1016/j.bmc.2018.06.012
Abstract

Chemical optimization of pyrazolopyridine 1, focused on cellular potency, isoform selectivity and microsomal stability, led to the discovery of the potent, selective and orally available PI3Kδ Inhibitor 5d. On the basis of its desirable potency, selectivity and pharmacokinetic profiles, 5d was tested in the trinitrophenylated aminoethylcarboxymethyl-Ficoll (TNP-Ficoll)-induced antibody production model, and showed higher antibody inhibition than a 4-fold oral dose of the starting compound 1. These excellent results suggest that 5d is a potential candidate for further studies in the treatment of autoimmune diseases and leukocyte malignancies.

Keywords

Isoform selectivity; PI3Kδ inhibitor; Pyrazolopyridine.

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